Recent advances in targeting COX-2 for cancer therapy: a review

Asmaa E Kassab

doi:10.1039/d5md00196j

. 2025 Apr 21. Online ahead of print. doi: 10.1039/d5md00196j

Recent advances in targeting COX-2 for cancer therapy: a review

Asmaa E Kassab ^a

PMCID: PMC12082340 PMID: 40386345

Abstract

Cyclooxygenase-2 (COX-2) is involved in the production of prostaglandins and thromboxanes, which control biological processes like inflammation, angiogenesis, and cell division. Numerous premalignant tissues and many human malignant tumors overexpress COX-2. Metabolites from COX-2 may support tumor growth, transformation, invasion, metastatic dissemination, premalignant hyperproliferation, downregulation of apoptosis, and tumor survival. COX-2 also triggers activity like cancer stem cells (CSCs). Populations of CSCs isolated from many cancer types are linked to overexpression of COX-2. Using nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of solid tumors, including colon, stomach, and esophageal malignancies. The anticancer potential of NSAIDs is mediated via COX-2 dependent or COX-2 independent pathways. For cancer patients, COX-2 may be a crucial target for therapeutic and chemoprotective measures. This review introduces the involvement of COX-2 in cancer via different pathways and provides a comprehensive review of the most recent updates on COX-2 inhibitors as potential anticancer candidates. This review aims to spark fresh thinking in the pursuit of more logical COX-2 inhibitor designs that may effectively treat cancer.

This review introduces the role of COX-2 in cancer through various pathways and provides a comprehensive overview of the most recent updates (2020–2024) on COX-2 inhibitors as potential anticancer agents.

1. Introduction

Cancer is predicted to become the major cause of death by the end of this century; it is currently the second most common cause of premature mortality worldwide, after cardiovascular diseases. Healthcare systems face significant strain and demand due to cancer. With an estimated global cost of $25.3 billion in 2017 and a projected cumulative cost of $25.2 trillion between 2020 and 2050, its economic impact is extremely significant.¹ The International Agency for Research on Cancer (IARC) and the World Health Organization (WHO) released the global cancer statistics 2022 in April 2024. The statistics highlight the incidence and mortality of 36 cancers across 185 nations and territories globally. Worldwide, a projected 19.96 million new cases of cancer and 9.74 million cancer-related deaths occurred in 2022. According to projections based on demographics, there will be more than 35 million new cases of cancer by 2050.²

2. Inflammation and cancer

In addition to being clonal progenitors of dysregulated cancer cells, tumors enhance their development and survival by creating a complex and extremely dynamic microenvironment that includes immune cells, endothelial cells, extracellular matrix, and numerous cytokines and growth factors.^3,4 Crucially, the microenvironment of all tumors is largely composed of inflammatory cells and the biological mediators of inflammation.⁵ In certain malignancies, inflammatory problems occur before the cancer develops; for instance, colon cancer is linked to inflammatory bowel illness. On the other hand, in tumors that are epidemiologically unconnected to overt inflammatory conditions, an oncogenic alteration may induce tumor-promoting inflammation.^6,7 Tissue remodeling, angiogenesis, cancer cell survival, metastasis, and immune evasion are only a few of the tumor-promoting impacts of this “smoldering” inflammation in the microenvironment.^5,8

Pleiotropic effects of chronic inflammatory mediators are implicated in the development of cancer,⁹ so chronic inflammation as an important risk factor has a critical role in the emergence of cancer.^9–12 Up to 25% of human cancers are linked to bacterial and viral infections as well as chronic inflammation.¹³ Certain irritants cause tissue damage, and the resulting chronic inflammation increases cell proliferation and may increase the chance of neoplasms when combined with other cancer risk factors.¹⁴ Prolonged chronic inflammation causes genomic instability, activates pro-oncogenes and/or inactivates suppressor genes, and induces malignancies by fostering the survival and proliferation of tumor cells.¹⁵ Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), fibroblasts, and lymphocytes are examples of inflammatory cells that are recruited to inflammatory areas. There, they target pathogens and produce cytokines to further trigger inflammation, immunological responses, and cell proliferation.¹⁶ Numerous carcinogenic variables have been linked to chronic inflammation. These factors include pro-inflammatory cytokines, pro-angiogenic and growth-promoting factors, anti-apoptotic and invasion-promoting factors, inflammatory enzymes, and prostaglandins, which are released by tumor cells or cells from the tumor microenvironment, such as stromal cells, endothelial cells, or host infiltrating cells.⁹ Additionally, these mediators and factors can damage cellular DNA and hinder the DNA damage repair response, which aids in cancer initiation and progression.¹⁰

2.1. Eicosanoids

Eicosanoids (prostaglandins, leukotrienes, and lipoxins) are signaling lipids derived from arachidonic acid (AA). They are a family of oxygenated metabolites of eicosapolyenoic fatty acids which are produced by both enzymatic and nonenzymatic processes. Despite being initially identified for their ability to trigger biological reactions such as smooth muscle contraction, edema, and platelet aggregation, eicosanoids are now understood to affect a variety of processes, from immunological responses and inflammation to cancer.¹⁷ Every tissue and cell type in the mammalian system produce eicosanoids, which appear to be involved in the majority of physiological processes. Thus, eicosanoids – also referred to as autocoids or tissue hormones – are thought to constitute the biggest family of local mediators.¹⁸ The three main enzymatic oxygenation processes that produce eicosanoids involve three different families of enzymes: lipoxygenases (LOXs), epoxygenases (EPOXs), and cyclooxygenases (COXs) (Fig. 1). The COXs (formerly known as prostaglandin [PG] H synthases) and LOXs are the most abundant and well-characterized enzymes that are important in inflammation and cancer. They oxygenate AA to produce a range of two-series prostanoids and four-series leukotrienes (LTs).^19,20

2.2. COX isoforms

There are three members of the human COX family: COX 1–3. Most tissues contain COX-1, an enzyme needed for housekeeping that keeps PGs at a low level and maintains the equilibrium of numerous physiological functions. An alternate splicing product of COX-1, COX-3 plays a role in controlling fever and discomfort.²¹ Even though the COX-1 and COX-2 isoforms are produced by various genes of varying sizes and result in unique mRNA sequences, the proteins' sequences and three-dimensional structures are remarkably similar.²² The basic sequences of human COX-l and COX-2 polypeptides are 61% similar.^23,24 The product produced by the two catalytic sites, the peroxidase site and the COX site, as well as the substrate and AA, are identical. The active COX sites in the various isoforms have nearly identical detailed structures.²²

2.3. The involvement of COX-2 in cancer and other disease pathways

Growth factors and cytokines are examples of pro-inflammatory and mitogenic stimuli that can affect the production of COX-2, an inducible enzyme. Through its involvement in the regulation of cell proliferation, cell transformation, tumor growth, tumor metastasis, and invasion, COX-2 plays a significant role in the creation of metaplastic and dysplastic tissue as well as in the initiation and progression of cancer.^25,26 The tumor promoter phorbol 12-myristate 13-acetate (PMA) and the cytokine interleukin-l (IL-1) induce the COX-2 transcript in vascular endothelial cells. Both transcriptional activation and post-transcriptional control of COX-2 mRNA stability are involved in the stimulation of endothelial cells by IL-lα.^23,24 COX-2 is an enzyme required for the metabolic conversion of AA to PGs, such as PGE2, a key mediator of angiogenesis and inflammation. Numerous investigations have demonstrated that several human cancers such as breast,²⁷ pancreatic,²⁸ prostate,²⁹ lung,^30,31 bone,^32–34 bladder,³⁵ and colon cancers³⁶ overexpress COX-2. Patients who had tumors with elevated COX-2 levels had much lower survival rates, and those tumors appeared to be more aggressive.³⁷ Several epidemiologic studies have found a negative relationship between the risk of colon cancer and frequent use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin,^38–42 which may indicate that abnormal COX activity plays a role in colorectal neoplasia. Both selective COX-2 inhibitors and nonselective NSAIDs have demonstrated efficacy in lowering tumor incidence in mouse models of intestinal carcinogenesis, supporting this theory.⁴³ COX-2 and cancer have been definitively linked by two complementary genetic techniques. In mouse skin, a lack of COX-2 prevents the development of chemically generated papillomas.⁴⁴ In a mouse model of colorectal cancer, the genetic ablation of COX-2 dramatically lowers tumor size and incidence. Compared to COX-2 wildtype mice, the incidence of intestinal adenoma decreased by 66% in COX-2 heterozygotes and 86% in COX-2 knockout animals.⁴⁵

Additionally, increased COX-2 expression may play a role in the development of several diseases, including adolescents with rheumatoid arthritis, ankylosing spondylitis, epilepsy, diabetes, Alzheimer's disease (AD), Parkinson's disease, and schizophrenia.^46–49 The COX-2 enzyme plays a crucial role in normal synaptic activity and plasticity and is linked to acetylcholine (Ach), tau protein, and beta-amyloid (Aβ), the primary causes of AD. It also plays a role in the development of amyloid plaques and neurofibrillary tangles in the brain. The kinase enzymes cyclin dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK-3β), which are known to contribute to tau phosphorylation and are closely linked to AD, are related to the COX-2 enzyme. Consequently, using medications like COX-2 inhibitors to treat AD may be a promising strategy.⁴⁷ Similarly, COX-2 is a key player in the pathophysiology of Parkinson's disease. COX-2 inhibition is still a promising target for neuroprotective treatment that aims to reduce or stop the disease's course.⁴⁸

Regarding diabetes, research on obese mice has shown that insulin resistance can result from the COX-2 pathway's malfunction because prostaglandin-mediated mesenteric leakage occurs, so COX-2 is a useful therapeutic target to lower insulin resistance. Celecoxib, a selective COX-2 inhibitor, reduced insulin resistance in obese mice when administered concurrently.^50–53

2.3.1. The involvement of COX-2 in cancer via the PG-dependent pathway

The manufacture of PGs in inflammatory and malignant tissues is aided by COX-2, which is not detectable in most normal tissues and is triggered by cytokines, growth factors, oncogenes, and tumor promoters.⁵⁴ Sustained PGE2 biosynthesis and constitutive expression of COX-2 seem to be key factors in the development and advancement of cancer. PGE2 can mediate these effects via a variety of signaling mechanisms, such as up-regulation of vascular endothelial growth factor (VEGF) production, resulting in angiogenesis, enhanced cell proliferation, and the potential for invasion and metastasis,⁵⁵ increasing invasion and metastasis through matrix metalloproteinase (MMP-2 and MMP-9) activation,⁵⁶ activation of the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K)/AKT pathways leading to upregulation of epidermal growth factor receptor (EGFR),⁵⁷ inhibition of programmed cell death through induction of BCL-2 expression⁵⁸ or elevation of transcription of the antiapoptotic mediator nuclear factor κBNF-kB.⁵⁹ By increasing the manufacture of estrogen, PGs may also indirectly promote proliferation in breast tissue. One significant organ-site-specific effect of COX-2 overexpression in breast cancer may be PG-mediated estrogen overproduction.⁶⁰ In adipose stromal cells, PGE2 has been demonstrated to enhance aromatase activity and induce promoter switching of the aromatase gene CYP19 to promoter II, which is typically utilized in adipose tissue next to breast cancers.^61,62 The immunological suppression linked to PGs may be attributed to the antiproliferative effects of PGs, which inhibit the growth of some cells, especially immune system cells. By allowing tumors to evade immune monitoring that could otherwise restrict tumor growth, PG-mediated immune suppression may be a factor in carcinogenesis⁶³ (Fig. 1).

2.3.2. The involvement of COX-2 in cancer via PG-independent pathways

2.3.2.1. Mutagenesis

Increased synthesis of mutagens such as malondialdehyde, which has strong mutagenic activity due to its capacity to form adducts with deoxynucleosides and hence promote frameshifts and base-pair substitutions, is a consequence of COX-2 overexpression.⁶³ Heterocyclic amines, aromatic amines, and dihydrodiol derivatives of polycyclic hydrocarbons can all undergo oxidation to produce further carcinogens.⁶⁴ Therefore, overexpression of COX-2 may cause DNA damage, which would aid in the development of cancer (Fig. 2).

2.3.2.2. Angiogenesis

COX-2 is involved in angiogenesis via its contribution to tumor vascularization. Selective COX-2 inhibitors reduce angiogenesis in several models in vivo, whereas they decrease endothelial tubule formation in vitro.^65–69 VEGF, basic fibroblast growth factor (FGF), transforming growth factor β-1 (TGF-β), platelet-derived growth factor (PDGF), and endothelin-1 are among the proangiogenic factors that COX-2 appears to aid in producing⁶⁶ (Fig. 2).

2.3.2.3. Cell motility, invasiveness, and metastasis

COX-2 expression has been shown to positively correlate with both in vivo metastasis and in vitro cancer cell invasion and motility. In intestinal epithelial cells in rats, COX-2 overexpression exhibits several changed traits, involving heightened extracellular adhesion matrix.^70,71 Furthermore, MMP enzymes that can break down the basement membrane are expressed and activated more when COX-2 expression in Caco-2 cells is stable, which is likely why these cells are seen to be more invasive.⁷² Moreover, MMP-2 and MMP-9 secretion was reduced in the human prostate tumor cell line DU-145 when COX-2 was inhibited.⁷³ Cell adhesion and motility may potentially be impacted by COX-2. In vitro and in vivo, COX-2 inhibitors have been shown to reduce tumor invasiveness, cell migration, and cell adhesion,^74–77 and perhaps as a result of changes in cellular dynamics, such as elevated MMP-2 expression and decreased E-cadherin expression, COX-2 expression increases tumor invasiveness and adhesiveness to external proteins^71,74–76 (Fig. 2).

2.3.2.4. Apoptosis

As one of the primary mechanisms of carcinogenesis, diminished apoptosis is believed to promote carcinogenesis by allowing cells that have acquired mutations to survive.⁷⁸ Numerous investigations have shown a link between elevated COX-2 expression and apoptosis suppression in a range of tumor types such as gliomas and colorectal, breast, esophageal, lung, pancreatic, prostate, and head and neck cancers.^79,80 Increased BCL-2 expression and decreased transforming growth factor-β2 (TGF-β2) levels are linked to a decrease in apoptosis in cells that overexpress COX-2.⁷⁴ Since AA promotes apoptosis possibly via activation of caspase-3 or conversion to ceramide,^74,81 increased COX-2 expression may prevent apoptosis by boosting AA conversion to PG^82,83 (Fig. 2).

2.3.3. The involvement of COX-2 in the maintenance of CSC populations

There is mounting evidence that cancer is a stem cell disease, with tumors made up of a mixture of cells that are genetically and functionally unique and contribute to tumor growth, as well as a tiny number of cancer stem cells (CSCs) that can promote tumor initiation, resistance to therapy, tumor repopulation, and metastasis. Normal hematopoietic stem cells (HSCs) and CSCs share many key characteristics, such as the capacity for self-renewal and multilineage differentiation. CSCs also accelerate the growth of tumors because they are the only ones with the capacity to continuously grow the tumor and produce a wide variety of differentiated progeny that comprise most of the tumor mass.^84–87 As an evolutionarily conserved regulator of HSCs, PGE2 has been hailed in the context of stem cell biology.⁸⁸ The capacity to develop into spheroid colonies under specific serum-free culture conditions that promote the growth of undifferentiated cells is a functional indicator of CSCs.⁸⁹ Compared to cells that express modest levels of COX-2, those that overexpress it show higher clonogenicity and sphere-forming efficiency.^90–92 It has been demonstrated that the COX-2/PGE2 axis is necessary for HSC production,⁹³ proliferation,^94,95 hematopoietic lineage maintenance,⁹⁶ and bone marrow recovery after irradiation injury.^93,97 By stabilizing β-catenin, PGE2 increases the activation of Wnt, a crucial regulator of stem cell self-renewal, throughout embryogenesis. Wnt-mediated regulation of HSC development is also PGE2-dependent.⁸⁸ Populations of CSCs isolated from many cancer types, such as breast,^98–101 colon,^102,103 and others, are linked to the overexpression of COX-2. The CSC markers CD44, CD133, Oct3/4, LGR5, SOX-2, and ALDH are co-expressed with COX-2 (ref. 104–109) (Fig. 3).

3. COX-2 inhibitors as anticancer agents

Many clinical, epidemiologic, and experimental investigations indicated that NSAIDs, such as ibuprofen and naproxen, and selective COX-2 inhibitors, such as celecoxib, have the potential as anticancer drugs.¹¹⁰ The administration of COX-2 inhibitors has been shown to reduce cancer risk by almost 68%.¹¹¹ COX-2 inhibition is related to the reduction of cancer recurrence and the increase in patient survival.¹¹² Long-term NSAID use is linked to a decreased risk of cancer-related mortality.¹¹⁰ Certain COX-2 inhibitors have been studied as chemo-preventive and possibly chemotherapeutic drugs because COX-2 is overexpressed in various premalignant lesions and neoplasms.^113–115 Inhibitors of COX-2 have demonstrated antitumor properties against various malignancies, including those of the human colon, breasts, lungs, and prostate.^116–122 COX-2 inhibition led to the regression of preexisting tumor foci and a decrease in the creation of new tumors. In several in vivo models, COX2 inhibitors have shown a dramatic reduction in tumor volume, which has led to a >10-fold decrease in tumor surface area.^116,123 In a sarcoma-based model of bone metastatic disease, specific inhibition of COX-2 may reduce tumor growth, bone damage, and cancer pain.¹²⁴ The National Cancer Institute (NCI) and Johns Hopkins University are sponsoring a phase II trial to examine the possibility of the COX-2 inhibitor celecoxib as a neoadjuvant before prostatectomy.¹²⁵ In Apc Min mice and other murine models of familial adenomatous polyposis, tumor formation is inhibited by selective COX-2 inhibitors such as celecoxib¹²⁶ and rofecoxib.¹²⁷ These drugs are already being used in clinics to prevent colon cancer.¹²⁸ COX-2 inhibitors have acceptable side effects, are reasonably priced when compared to conventional cancer treatments, and can make cancer cells more sensitive to radiation, chemotherapy, and other treatments.^112,129 COX-2 inhibitors were used as adjuvants in conjunction with chemotherapy and/or radiation therapy. The antitumoral activity of chemotherapeutic drugs such as sorafenib,¹³⁰ 5-fluorouracil (5-FU), bleomycin, and irinotecan¹²⁹ has been shown to increase synergistically with such a combination. The Food and Drug Administration (FDA) has approved celecoxib as a chemo-preventive treatment for precancerous colonic polyps in familial adenomatous polyposis (FAP) patients.¹³¹

4. The mechanistic pathways of anticancer potential of COX-2 inhibitors

COX-2 inhibition results in the suppression of PGE₂ which can promote tumor growth by binding its receptors and activating signaling pathways that control cell proliferation, migration, apoptosis, and/or angiogenesis.¹³² By preventing the expression of angiogenic factors and the migration of vascular endothelial cells, COX-2 inhibitors reduce angiogenesis and tumor formation.¹³³ In human tumors, selective COX-2 inhibitors at low doses promote apoptosis and decrease cell proliferation in the colon, stomach, esophagus, tongue, brain, lungs, and pancreas.¹¹⁰ Celecoxib has been demonstrated to cause apoptosis in K562 cells¹³⁴ through cytochrome C release, poly (ADP-ribose) polymerase (PARP) cleavage, BCL-2 downregulation, and membrane potential reduction. As a result of the downregulation of beta1-integrin, a cell adhesion molecule, mediated by the COX-2 inhibitor tilmacoxib (JTE-522), cancer cells were less able to stick to and migrate on the extracellular matrix, two processes that are essential for the development of cancer metastases.¹³⁵ BCL-2 downregulation and subsequent apoptosis,¹³⁶ proapoptotic Bax protein upregulation and decreased BCL-XL protein,¹³⁷ mitochondrial membrane potential (Δψ_m) loss and caspase-3 activation,^138–140 or a marked reduction in Akt activation¹⁴¹ can all mediate the antitumor potential of COX-2 inhibitors (Fig. 4).

Consequently, there has been a great deal of excitement in scientific research about the potential of COX-2 inhibitors as anticancer agents. Herein, we are going to provide a comprehensive review of newly developed COX-2 inhibitors (2020–2024) which have shown promising results as anticancer agents.

5. The anticancer activity of COX-2 inhibitors

Research into new selective inhibitors with dual anti-inflammatory and anticancer potential has increased due to the discovery that COX-2 is a crucial therapeutic target in the development of anticancer drug candidates.

Building on this foundation, Akhtar et al.¹⁴² designed and synthesized pyrazole–pyrazoline hybrids as cancer-associated selective COX-2 inhibitors. The (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) (MTT) growth inhibition assay was used to screen all pyrazole–pyrazoline hybrids for their in vitro anticancer activity against five cell lines: MCF-7, A549, SiHa, COLO205, and HepG2 cells. 5-FU was used as the study's positive control. Compound 1 (Table 1) exhibited the most prominent anticancer activity against A549, SiHa, COLO205, and HepG2 cells, as evidenced by IC₅₀ values of 2.09, 4.94, 4.54, and 4.86 μM. Additionally, it had an IC₅₀ value greater than 50 μM against normal cells (cell line HaCaT). The pyrazole–pyrazoline hybrids' anti-inflammatory properties in vitro were also assessed. Compounds with notable anti-inflammatory and anti-cancer properties were investigated further for COX inhibition. Compared to the other compounds, compound 1 had the greatest COX-2 inhibitory potential with an IC₅₀ value of 1.09 μM and a COX1/COX2 selectivity index (SI) of 80.03. The docking results revealed that compound 1 uses both hydrophobic and hydrophilic interactions to fit most easily in the COX-2 binding pocket.

Table 1. COX-2 inhibitors with anticancer potential.

Compound	Biological activity	Reference
1	A549 cells IC₅₀ = 2.09 μM; SiHa cells IC₅₀ = 4.94 μM; COLO205 cells IC₅₀ = 4.54 μM; HepG2 cells IC₅₀ = 4.86 μM; COX-2 IC₅₀ = 1.09 μM	142
2	PC3 cells IC₅₀ = 1.38 μM, SI = 432.30; MCF-7 cells IC₅₀ = 46.09 μM, SI = 12.94; ↑ Bax expression; ↓ BCL-2 expression; 91% COX-2 inhibition at 50 μM concentration	143
3	EKVX GI₅₀ = 1.73 μM; HOP-92 GI₅₀ = 0.605 μM; NCI-H226 GI₅₀ = 3.79 μM; SNB-19 GI₅₀ = 2.45 μM; SNB-75 GI₅₀ = 1.24 μM; U251 GI₅₀ = 0.65 μM; IGROV1 GI₅₀ = 0.70 μM; OVCAR-4 GI₅₀ = 0.33 μM; OVCAR-5 GI₅₀ = 4.03 μM; RXF-393 GI₅₀ = 1.75 μM; MDA-MB-231/ATCC GI₅₀ = 2.25 μM; HS578 T GI₅₀ = 1.60 μM; BT-549 GI₅₀ = 7.24 μM; T-47D GI₅₀ = 2.97 μM; COX-2 IC₅₀ = 0.91 μM	144
4	HCT116 IC₅₀ = 6.43 μM; A549 IC₅₀ = 9.62 μM; A375 IC₅₀ = 8.07 μM; EGFR IC₅₀ = 2.80 μM; ↑ apoptosis (28.35%) in HCT116 cells; COX-2 IC₅₀ = 37.5 μM	145
5	HeLa IC₅₀ = 9.71 μM; MCF-7 IC₅₀ = 16.43 μM; for HCT116 IC₅₀ = 2.34 μM; HepG2 IC₅₀ = 12.51 μM; ↑ apoptosis; stops the cell cycle at the G1 stage; COX-2 IC₅₀ = 0.28 μM	146
6	MCF-7 IC₅₀ = 4.37 μM; ↑ apoptosis; cell-cycle arrest in the G2 phase; COX-2 IC₅₀ = 0.22 μM	147
7	HeG2 IC₅₀ = 8.71 μM; HCT-116 IC₅₀ = 7.66 μM; MCF-7 IC₅₀ = 6.93 μM; PC3 IC₅₀ = 11.45 μM; HeLa IC₅₀ = 5.86 μM; COX-2 IC₅₀ = 1.08 μM	148
8	A549 IC₅₀ = 8.9 μM; HepG2 IC₅₀ = 2.37 μM; MCF-7 IC₅₀ = 2.69 μM; ↑ apoptosis; halted G2/M cells; ↓ BCL-2 (0.54-fold change); ↑ caspase-9 (7.36-fold change); ↑ Bax (4.99-fold change); COX-2 IC₅₀ = 0.06 μM	149
9	MCF-7 IC₅₀ = 0.16 μM; A2780 IC₅₀ = 0.22 μM; HT29 IC₅₀ = 0.60 μM; CDK2 IC₅₀ = 0.63 μM; ↑ sub G1 population, and G1-phase; ↑ apoptosis in MCF-7 cells; COX-2 IC₅₀ = 10.79 μM	150
10	MCF-7 IC₅₀ = 0.67 μM; 95% COX-2 inhibition at 50 μM concentration	151
11	HCA7 IC₅₀ = 137.3 μM; HT29 IC₅₀ = 15.42 μM; HCT116 IC₅₀ = 75.35 μM; COX-2 IC₅₀ = 0.04 μM	152
12	MCF-7 IC₅₀ = 0.03 μM; ↑ apoptosis (52.81%); ↓ BCL-2; ↑ Bax; ↑ caspase-3; COX-2 IC₅₀ = 0.07 μM	153
13	HT-29 IC₅₀ = 4.1 μM; PaCa-2 IC₅₀ = 3.7 μM; A375 IC₅₀ = 3.9 μM; H-460 IC₅₀ = 2.7 μM; Panc-1 IC₅₀ = 3 μM; EGFR IC₅₀ = 0.5 μM; COX-2 IC₅₀ = 2.47 μM	154
14	PIM-1 IC₅₀ = 2.96 μM; 5-LOX IC₅₀ = 3.54 μM; COX-2 IC₅₀ = 0.091 μM; Caco-2 IC₅₀ = 0.051 μM; ↑ apoptosis (66.38%) and ↑ caspases 3/7 (55.68%) in Caco-2 cells; HCT-116 IC₅₀ = 0.060 μM; ↑ apoptosis (65.27%), ↑ caspases 3/7 (53.62%) in HCT-116 cells	155
15	A549 IC₅₀ = 24.29 μg mL⁻¹; DLD1 IC₅₀ = 19.27 μg mL⁻¹; MCF-7 IC₅₀ = 20.28 μg mL⁻¹; COX-2 IC₅₀ = 0.07 μM	156
16	A549 IC₅₀ = 10 μg mL⁻¹; Caco-2 IC₅₀ = 14 μg mL⁻¹; ↑ apoptosis; arrested the cell cycle at the G0/G1 phase; ↑ caspases 3; 28.81% COX-2 inhibition in A549 Cells; 46.78% COX-2 inhibition in Caco-2 cells	157
17	HT-29 IC₅₀ = 5.46 μM; COX-2 IC₅₀ = 0.05 μM	158
18	Mean GI₅₀ = 0.26 μM; EGFR IC₅₀ = 0.19 μM; HER2 IC₅₀ = 0.07 μM; arrested the cell cycle at the G2/M phase; ↑ apoptosis; COX-2 IC₅₀ = 6.94 μM	159
19	MCF-7 IC₅₀ = 0.81 μM; HepG2 IC₅₀ = 0.96 μM; HCT-116 IC₅₀ = 1.12 μM; EGFR IC₅₀ = 0.4 μM; COX-2 IC₅₀ = 0.46 μM	160
20	HepG-2 IC₅₀ = 11.47 μM; HCT-116 IC₅₀ = 8.45 μM; MCF-7 IC₅₀ = 6.77 μM; induced cell cycle arrest at G1 and S phases; ↑ apoptosis; COX-2 IC₅₀ = 0.069 μM	161
21	MCF-7 IC₅₀ = 5.35 μM; MDA-MB-231 IC₅₀ = 11.02 μM; ↑ apoptosis; induced G0/G1 phase cell cycle arrest; 50.26% COX-2 inhibition	162
22	MCF-7 IC₅₀ = 4.85 μM; 1.2-fold ↑ S phase cell population; ↑ apoptosis; ↑ p53; ↑ Bax; ↓ BCL-2; COX-2 IC₅₀ = 0.54 μM	163
23	MCF-7 IC₅₀ = 7.75 μM; cell cycle arrest at the G2/M phase; ↑ apoptosis; ↑ p53; ↑ Bax; ↓ BCL-2; ↑ caspase-7; COX-2 IC₅₀ = 17.58 μM	164
24	MCF-7 IC₅₀ = 1 nM; A549 IC₅₀ = 1 nM; A498 IC₅₀ = 2 nM; HepG2 IC₅₀ = 9 nM; cell cycle arrest at sub-G1 and G2/M phases; ↑ apoptosis; COX-2 IC₅₀ = 0.16 μM	165
25	Panc-1 IC₅₀ = 1.8 μM; H-460 IC₅₀ = 1.2 μM; HT-29 IC₅₀ = 1.2 μM; A375 IC₅₀ = 3.2 μM; PaCa-2 IC₅₀ = 2.1 μM; EGFR IC₅₀ = 0.8 μM; COX-2 IC₅₀ = 1.27 μM	166
26	A549 IC₅₀ = 74.64 μM; MCF-7 IC₅₀ = 18.75 μM; HepG2 IC₅₀ = 84.29 μM; ↓ COX-2 gene expression in MCF-7 cells	167
27	MCF-7 IC₅₀ = 2.85 μM; HT-29 IC₅₀ = 2.12 μM; cell cycle arrest at the G1/S phase; ↑ apoptosis; ↑ Bax; ↓ BCL-2; ↑ caspase-3/9; EGFR IC₅₀ = 0.083 μM; Topo-I IC₅₀ = 0.020 μM; COX-2 IC₅₀ = 0.043 μM	168
28	A549 IC₅₀ = 4.53 μM; ↑ apoptosis; ↑ caspase-3; COX-2 IC₅₀ = 8.86 μM	169
29	MCF-7 IC₅₀ = 9 μM; HEP-3B IC₅₀ = 12 μM; HCT-116 IC₅₀ = 8 μM; A549 IC₅₀ = 3.3 μM; F180 IC₅₀ = 16.5 μM; aromatase IC₅₀ = 30.30 μM; EGFR IC₅₀ = 0.066 μM; B-RAFV600E IC₅₀ = 0.05 μM; cell cycle arrest at the G0–G1 phase; ↑ apoptosis; COX-2 IC₅₀ = 0.363 μM	170
30	MCF-7 IC₅₀ = 0.73 μM; A549 IC₅₀ = 1.64 μM; EGFR IC₅₀ = 0.043 μM; HER-2 IC₅₀ = 0.032 μM; COX-2 IC₅₀ = 0.349 μM	171
31	A549 IC₅₀ = 20.28 μM; A375 IC₅₀ = 16.08 μM; ↓ COX-2 expression in A549 and A375 cells	172
32	HL-60 (TB) IC₅₀ = 11.96 μM; SK-OV-3 IC₅₀ = 9.46 μM; MCF-7 IC₅₀ = 6.68 μM; cell cycle arrest at the S and G2/M phases; ↑ apoptosis; COX-2 IC₅₀ = 69.79 nM	173
33	Colo 205 IC₅₀ = 30.79 μM; B16F1 IC₅₀ = 74.15 μM; COX-2 IC₅₀ = 0.191 μM	174
34	Colo 205 IC₅₀ = 1.66 μM; EGFR^WT IC₅₀ = 0.096 μM; cell cycle arrest at the G1 phase; ↑ apoptosis; ↑ caspase-3; COX-2 IC₅₀ = 1.28 μM	175
35	MCF-7 IC₅₀ = 3.12 μM; K-MEL-5 IC₅₀ = 4.28 μM; IGROV1 IC₅₀ = 4.13 μM; aromatase IC₅₀ = 16.50 μM; cell cycle arrest at the G2/M phase; ↑ apoptosis; COX-2 IC₅₀ = 0.23 μM	176
36	MCF-7 IC₅₀ = 93.03 μg mL⁻¹; ↑ apoptosis; COX-2 IC₅₀ = 63.45 μg mL⁻¹	177
37	70.07% growth inhibition of BT-459 cells; EGFR^L858R/T790M IC₅₀ = 4.03 μM; 15-LOX IC₅₀ = 1.95 μM; COX-2 IC₅₀ = 5.04 μM	178
38	53.33% growth inhibition of MCF-7 cells; COX-2 IC₅₀ = 0.05 μM	179
39	HePG-2 IC₅₀ = 2.31 μM; MCF-7 IC₅₀ = 3.81 μM; HCT-116 IC₅₀ = 10.07 μM; cell cycle arrest at the G1 phase; ↑ apoptosis; COX-2 IC₅₀ = 0.06 μM	180
40	Caco-2 IC₅₀ = 9.6 nM; COX-2 IC₅₀ = 7.69 nM	181
41	HeLa IC₅₀ = 4.61 μM; MCF-7 IC₅₀ = 10.81 μM; MB-MDA-231 IC₅₀ = 2.09 μM; cell cycle arrest at the G2/M phase; ↑ apoptosis; COX-2 IC₅₀ = 0.17 μM	182
42	HepG-2 IC₅₀ = 3.98 μM; HCT-116 IC₅₀ = 8.70 μM; MCF-7 IC₅₀ = 7.85 μM; CDK2 IC₅₀ = 0.614 μM; cell cycle arrest at the G1 phase; ↑ apoptosis; ↑ Bax/BCL-2; COX-2 IC₅₀ = 0.075 μM	183
43	HepG2 IC₅₀ = 4.13 μM L⁻¹; Eac-109 IC₅₀ = 5.99 μM L⁻¹; MDA-MB-231 IC₅₀ = 7.68 μM L⁻¹; Topo I inhibition; cell cycle arrest at the G1 phase; ↑ apoptosis; ↑ Bax/BCL-2; ↑ caspase3/9; ↑ P21 and P53, ↓ CDK4 and cyclin D1; COX-2 IC₅₀ = 69.92 nM L⁻¹	184
44	CaCo-2 IC₅₀ = 10.22 μM; Hep3B IC₅₀ = 4.84 μM; HeLa IC₅₀ = 1.57 μM; ↓ colonization of HeLa and HepG2 cells; ↑ ROS; ↑ apoptosis; ↓ formation of spheroid structures in Hep3B and HeLa cells; COX-2 IC₅₀ = 0.247 μM	185
45	A549 IC₅₀ = 40.14 μM; COX-2 IC₅₀ = 0.781 μM	186

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Based on the same strategy, several sulfonyl hydrazones were synthesized by Şenkardeş et al.¹⁴³ The cytotoxic activity of all synthesized compounds was assessed against L929 murine fibroblast, breast cancer (MCF-7), and prostate cancer (PC3) cell lines by adopting the MTT assay. With good selectivity, compound 2 (Table 1) exhibited the most potent anticancer activity against both cancer cells (IC₅₀ = 1.38 μM on PC3 with SI = 432.30 and IC₅₀ = 46.09 μM on MCF-7 with SI = 12.94). Subsequent research verified that compound 2 caused morphological changes in PC3 and MCF-7 cells and induced apoptosis by upregulating Bax expression and downregulating BCL-2. Furthermore, the molecule was shown to be the most effective COX-2 inhibitor, with 91% inhibition. Compound 2's molecular docking indicated a significant binding mode in charge of its anticancer action through COX-2 enzyme inhibition.

Continuing the search for effective anticancer scaffolds, Akhtar et al.¹⁴⁴ synthesized 6-(4-fluorophenyl)-pyrimidine-5-carbonitrile derivatives by the Biginelli condensation reaction. All synthesized compounds were chosen for one-dose anticancer screening after being submitted to the National Cancer Institute (NCI), USA. Compound 3 (Table 1) was found to be the most potent derivative and thus it was selected for five dose assays. Three response parameters, namely GI₅₀, TGI, and LC₅₀ for each cell line, were used to determine the results of compound 3's five-dose assays. Compound 3's growth inhibition GI₅₀ (MG-MID) value of 6.250 indicated significant broad-spectrum anticancer action. With selectivity indices of 1.653, 3.068, 1.949, and 5.012 for non-small cell lung cancer, CNS cancer, ovarian cancer, and renal cancer cell lines, respectively, it demonstrated exceptional potency against these cancers. Compound 3 demonstrated superior anticancer activity against ovarian OVCAR-4 cancer cells with a GI₅₀-value of 0.33 μM and a selectivity index of 4.84 compared to 5-FU, which showed a GI₅₀-value of 4.43 μM. Compound 3 was a selective COX-2 inhibitor (IC₅₀ = 0.91 μM) with a COX-1/COX-2 SI of 105.

Additional chemical scaffold diversity resulted in the design and synthesis of new indole-based 1,3,4-oxadiazoles as EGFR and COX-2 inhibitors by Sever et al.¹⁴⁵ Using the MTT assay, the cytotoxic effects of synthesized compounds were assessed against human colorectal cancer HCT116, lung adenocarcinoma A549, and melanoma cell lines A375. When compared to erlotinib (IC₅₀ = 17.86 μM, 19.41 μM, and 23.81 μM, respectively), compound 4 (Table 1) demonstrated the strongest anticancer activity against HCT116, A549, and A375 cell lines, with IC₅₀ values of 6.43 μM, 9.62 μM, and 8.07 μM, respectively. Additional mechanistic studies showed that compound 4 considerably increased apoptosis (28.35%) in HCT116 cells compared to erlotinib (7.42%) and greatly inhibited EGFR, with an IC₅₀ value of 2.80 μM compared to erlotinib (IC₅₀ = 0.04 μM). It exhibited moderate activity against COX-2 (IC₅₀ = 37.5 μM).

In another effort, a new class of aminophosphonate compounds containing sulfonamide were synthesized as potential anticancer agents and selective COX-2 inhibitors.

Employing the MTT method, the top hit compound 5 (Table 1) showed antiproliferative potential against many cancer cell lines (IC₅₀ values: 9.71 μM for HeLa, 16.43 μM for MCF-7, 2.34 μM for HCT116, 12.51 μM for HepG2). It demonstrated significant COX-2 inhibitory activity (IC₅₀ = 0.28 μM) with a COX-1/COX-2 SI of 172.32, much better than the control celecoxib. Compound 5 triggers apoptosis through a mitochondrial-dependent mechanism and stops the cell cycle at the G1 stage.¹⁴⁶

Complementing the previous work, Zhang et al.¹⁴⁷ developed several aminophosphonate compounds with a pyrazole component. A standard MTT-based colorimetric assay was used to evaluate the synthesized compounds' antiproliferative efficacy against six distinct cell lines (HeLa, SW480, MCF-7, HCT116, HepG2, and 293T cell lines). Compound 6 (Table 1) demonstrated outstanding COX-2 inhibitory efficacy (IC₅₀ = 0.22 μM) and antiproliferative activity against MCF-7 cells (IC₅₀ = 4.37 μM). Using the polymerase chain reaction and flow cytometry, compound 6's induction of apoptosis was verified. Subsequent research revealed that compound 6 induced cell-cycle arrest in the G2 phase and caused MCF-7 cells to undergo apoptosis via a route dependent on mitochondria.

In the same direction, several compounds were synthesized based on a 2-cyclopentyloxyanisole scaffold, and their anticancer activity was assessed in vitro by applying the MTT assay. The synthesized compounds exhibited significant antitumor activity (IC₅₀ range: 5.13–17.95 μM). Among the synthesized compounds, compound 7 (Table 1) demonstrated potent anticancer activity with IC₅₀ values of 8.71, 7.66, 6.93, 11.45, and 5.86 μM against the HeG2, HCT-116, MCF-7, PC3, and HeLa cancer cells. It was the most active inhibitor of COX-2, with an IC₅₀ value of 1.08 μM. Furthermore, compound 7 showed strong interactions at the COX-2 binding pocket.¹⁴⁸

Pursuing multitarget approaches, several 1,2,3-triazoles hybridized with pharmacophoric anticancer fragments were designed and synthesized using a multi-target design technique. These compounds are first-class simultaneous inhibitors of COX-2, 15-LOX, and tumor-related carbonic anhydrase enzymes. Several compounds were shown to be strong inhibitors of the COX-2 and 15-LOX enzymes. The tumor-associated hCA XII isoform was effectively inhibited at the nanomolar and sub-micromolar levels by the sulfonamide-bearing derivatives. The most active compounds in the aforementioned in vitro enzymatic assays were tested for their cytotoxic effects against normal human lung fibroblasts (WI-38) and three cancer cell lines namely, non-small cell lung cancer A549, liver cancer HepG2 and breast cancer MCF-7 cell lines, utilizing the sulforhodamine B (SRB) assay procedure. Celecoxib and 5-FU were used as reference drugs. Compound 8 (Table 1) showed significant growth inhibitory activity with single-digit micromolar IC₅₀ values (8.9, 2.37, and 2.69 μM against A549, HepG2, and MCF-7 cancer cell lines). It exhibited potent nanomolar inhibition of the COX-2 enzyme with an IC₅₀ value of 0.06 μM and a COX-1/COX-2 SI of 198. Two cancer cell lines' accumulation of 6-keto-PGF1α, a metabolite of COX-2 products, was inhibited, further demonstrating the COX-2 inhibitory action of compound 8. It induced apoptosis and halted the development of G2/M cells. It successfully downregulated the expression levels of the anti-apoptotic protein BCL-2 (0.54-fold change) while simultaneously upregulating those of caspase-9 (7.36-fold change) and the proapoptotic protein Bax (4.99-fold change).¹⁴⁹

The diversity of chemotypes continues, as Shawky et al.¹⁵⁰ developed two novel pyrrolizine-5-carboxamide series, and their anti-inflammatory and anticancer properties were assessed by adopting the MTT assay. When tested against three cancer cell lines (MCF-7, A2780, and HT29), the novel compounds demonstrated strong cytotoxicity (IC₅₀ = 0.10–22.96 μM) with SIs between 1 and 258. Additionally, these compounds had strong anti-inflammatory properties, which were mediated by COX-1/2 inhibition with COX-2 preferential inhibition. Compound 9 (Table 1) exhibited the highest cytotoxic activity against MCF-7, A2780, and HT29 cells (IC₅₀ values of 0.16, 0.22, and 0.60 μM). Apoptosis signal-regulating kinase 1 (ASK1), Aurora A, CDK2, CK1 alpha 1, GRK1, GSK3 alpha, MSK1, and PDK1 were concurrently inhibited by compound 9. It displayed the highest inhibitory activity against CDK2 (IC₅₀ = 0.63 μM). It increased the subG1 population and G1-phase and induced apoptosis in MCF-7 cells. Compound 9 showed moderate COX-2 inhibition with an IC₅₀ value of 10.79 μM.

Completing the exploration of the pyrazoline scaffold, Kumari et al.¹⁵¹ reported the design and synthesis of pyrazoline and isoxazole-bridged indole C-glycoside hybrids as potential anticancer agents. The anticancer potential of the synthesized derivatives was investigated by applying the MTT assay. Several hybrids showed specific toxicity against the breast cancer cell line (MCF-7) and low micromolar IC₅₀ = 0.67–4.67 μM. On the other hand, these hybrids did not harm the normal cell line (MCF-10A). Molecular docking studies corroborated mechanistic investigations that demonstrated that active hybrids block the COX-2 enzyme. Compound 10 (Table 1) exhibited significant antiproliferative activity against MCF-7 cells with an IC₅₀ value of 0.67 μM. COX-2 assay results revealed that compound 10 showed significant COX-2 inhibition (95% at 50 μM concentration).

Continuing with structural innovation, Sakr et al.¹⁵² reported the development of new quinazolinones conjugated with thioacetohydrazide, indole acetamide, or ibuprofen as specific COX-2 inhibitors with anticancer properties. The three synthesized series demonstrated equipotent COX-2 selectivity to celecoxib and higher COX-2 selectivity (SI = 254–398) compared to the previously reported quinazolinones and their NSAID equivalents. The antiproliferative activity of the synthesized quinazolinones was assessed using the (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay. Compound 11 (Table 1) demonstrated antitumor activity in the HCA7, HT29, and HCT116 cell lines with IC₅₀ values of 137.3, 15.42, and 75.35 μM. Results from the COX-1/2 enzyme assay and docking agreed with each other. COX-2 assay results revealed that compound 11 showed excellent COX-2 inhibition (IC₅₀ = 0.04 μM and SI of 317).

In the same direction, the cytotoxicity to several cell lines by adopting the MTT assay and the selective COX-2 inhibitory potency of a novel family of 3′-(mono, di, or tri-substituted phenyl)-4′-(4-(methylsulfonyl)phenyl) spiroisoxazoline derivatives containing an indanone spiro-bridge were assessed. The synthesized compounds' ability to form hydrogen bonds with COX-2 involving methyl sulfonyl, spiroisoxazoline, meta-methoxy, and fluoro functional groups was demonstrated by the docking data. With IC₅₀ values between 0.07 and 0.16 μM and COX-2 selectivity scores between 58.9 and 173, all synthesized compounds were selective inhibitors of the COX-2 isozyme. Spiroisoxazoline derivatives having a methoxy group at the meta-position of the C-3′ phenyl ring showed greater effectiveness and selectivity in inhibiting the COX-2 enzyme. Compound 12 (Table 1) demonstrated the best COX-2 inhibitory action (IC₅₀ = 0.07 μM) and COX-2 selectivity (SI = 173). With an IC₅₀ value of 0.03 μM, it demonstrated the most potent anticancer activity against MCF-7 cells. This value is comparable to that of doxorubicin (IC₅₀ of 0.062 μM). Compound 12 promoted breast cancer cell apoptosis (52.81%). Additionally, after being exposed to compound 12, the mRNA expression of BCL-2 dramatically decreased and that of Bax and caspase-3 greatly increased as compared to the control group. This finding may suggest that the observed apoptosis is caused by the activation of a mitochondrial-associated pathway.¹⁵³

Continuing along similar lines, Abdelgawad et al.¹⁵⁴ reported the design and synthesis of novel phenolic compounds as potential dual EGFR and COX-2 inhibitors. Compound 13 (Table 1) demonstrated strong COX-2 inhibition (IC₅₀ = 2.47 μM, SI of 3.99) and higher inhibitory efficacy against EGFR (IC₅₀ = 0.5 μM). Additionally, human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines were used to assess the final compounds' cytotoxic activities using the MTT assay. Compound 13 had the strongest cytotoxic activity against HT-29, PaCa-2, A375, H-460, and Panc-1 cell lines with IC₅₀ values of 4.1, 3.7, 3.9, 2.7, and 3 μM. To properly grasp the plausible binding mechanisms of target drugs within the EGFR and COX-2 binding sites, a virtual docking analysis was carried out which rationalized the significant in vitro activity.

Broadening the search for multifunctional agents, El-Miligy et al.¹⁵⁵ reported the discovery of a thymol–4-thiazolidinone hybrid acting as a multitarget inhibitor of colorectal cancer by simultaneous blocking of the key COX-2, 5-LOX, and PIM-1 kinase enzymes. In vitro, compound 14 (Table 1) potently inhibited the target key enzymes PIM-1 kinase, 5-LOX, and COX-2 with IC₅₀ values of 2.96, 3.54, and 0.091 μM. Additionally, it demonstrated caspase 3/7 (55.68% and 53.62%) activation dependent apoptosis (66.38% and 65.27%) in Caco-2 and HCT-116 human colorectal cancer cell lines, respectively. Adopting the MTT method using Caco-2 and HCT-116 human colorectal cancer cell lines, compound 14 inhibited cell proliferation in the two colon cancer cell lines in vitro with IC₅₀ values of 0.051 and 0.060 μM. In the in silico docking studies in the active site of the target, enzymes were concordant with the biological results.

Reinforcing this strategy, thiazole and thiazolidine-based pharmacophore molecules were synthesized to obtain dual COX-2 and 5-LOX inhibitory activity. The most promising derivative in the series (2-(diphenylamino)-4-(4-nitrophenyl)thiazol-5-yl)(naphthalen-1-yl)methanone 15 (Table 1) (COX-2 IC₅₀ = 0.07 μM) had an increased SI of 115.14 and COX-2 inhibitory potency comparable to the positive control etoricoxib (IC₅₀ = 0.07 μM). Using the MTT assay, compound 15's in vitro cytotoxicity was examined on L929 (fibroblast) cells, and then its in vitro anticancer activity was examined on three cell lines: A549 (human lung cancer), MCF-7 (human breast adenocarcinoma), and DLD1 (human colorectal adenocarcinoma). It showed less anticancer activity against all three cancer cell lines (A549 IC₅₀ = 24.29 μg mL⁻¹, DLD1 IC₅₀ = 19.27 μg mL⁻¹, MCF-7 IC₅₀ = 20.28 μg mL⁻¹) compared to doxorubicin. Compared to doxorubicin, compound 15 (IC₅₀ = 110.24 μg mL⁻¹) showed a higher safety profile against L929 cells, a normal cell line.¹⁵⁶

To further investigate structurally varied COX-2 inhibitors, Sever et al.¹⁵⁷ reported the design of triazolothiadiazines as potential anticancer agents for the targeted therapy of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Their cytotoxic effects on A549 human lung adenocarcinoma, Caco-2 human colorectal cancer, and CCD-19Lu human lung fibroblast cells were assessed using the MTT assay. In A549 and Caco-2 cells, the most potent compounds were assessed for their effects on COX-2, apoptosis, caspase-3, mitochondrial membrane potential, the cell cycle, and ultrastructural morphological alterations. Among these anticancer agents, 16 (Table 1) was the most effective and selective against the A549 and Caco-2 cell lines with IC₅₀ values of 10 and 14 μg mL⁻¹ and SIs of 50 and 35. In A549 cells, compound 16 induced early apoptosis, depolarized the mitochondrial membrane, and stopped the cell cycle at the G0/G1 phase. However, in Caco-2 cells, compound 16 activated the caspase-3-related intrinsic apoptotic pathway. Both cancer cell lines experienced apoptotic morphological alterations due to treatment with compound 16. It was discovered that this compound's specific COX-2 inhibitory activity (28.81% and 46.78% in A549 and Caco-2 cells) was linked to its cytotoxic and apoptotic effects in CRC. Molecular docking experiments revealed that compound 16 has a high affinity for the COX-2 active site.

Keeping in the same direction, Vahedpour et al.¹⁵⁸ reported the synthesis and biological evaluation of 1,3,5-trisubstituted 2-pyrazolines as novel COX-2 inhibitors with antiproliferative activity. A COX-2 pharmacophore SO₂CH₃ is incorporated into the developed structures at the para-position of the phenyl ring at C-5 of a pyrazoline scaffold. The developed compounds were evaluated for COX-1/COX-2 inhibition. In vitro, cell toxicity was also evaluated by conducting the MTT method using the HT-29 human colorectal cancer cell line. Significant COX-2 inhibition (IC₅₀ = 0.05 μM) and antiproliferative activity (IC₅₀ = 5.46 μM) were demonstrated by lead compound 17 (Table 1). According to molecular docking studies, the new pyrazoline-based derivatives engage with important COX-2 binding site residues through various hydrophobic and hydrogen-bond interactions.

In keeping with this, Abdel-Aziz et al.¹⁵⁹ synthesized a series of hydrazones incorporating a 4-methylsulfonylbenzene scaffold and their potential antitumor activity was analyzed by the NCI (USA). With a mean 50% cell growth inhibition (GI₅₀) of 0.26 μM, compound 18 (Table 1) was the most potent. It was nearly 65-fold more potent than celecoxib, 3-fold more potent than 5-FU, 30-fold more potent than erlotinib, and 9-fold more potent than gefitinib and sorafenib. With an IC₅₀ value of 6.94 μM, compound 18 exhibited the most inhibitory efficacy against COX-2. EGFR (IC₅₀ = 0.19 μM) and HER2 (IC₅₀ = 0.07 μM) were both markedly suppressed by compound 18. It caused the cell cycle arrest at the G2/M phase and induced apoptosis in HL60 cells. To investigate the method of interaction and the structural prerequisites for anticancer activity, molecular docking studies of 18 into the binding sites of COX-2, EGFR, and HER2 were conducted. Compound 18 bound in the COX-2-, EGFR-, and HER2-binding sites in a manner comparable to that of the co-crystallized inhibitors.

In pursuit of novel backbone frameworks, novel quinoxaline derivatives have been synthesized and screened for their in vitro anticancer and COX inhibitory activities. Most of the synthesized compounds had strong COX-2 inhibitory and anticancer properties. When the MTT assay was performed, compound 19 (Table 1) was the most effective and had strong anticancer activity against breast (MCF-7), liver (HepG2), and colon (HCT-116) carcinoma cell lines with IC₅₀ values of 0.81, 0.96 and 1.12 μM. The EGFR-TK assay was performed with erlotinib as a positive control to investigate a potential anticancer mechanism of the most powerful molecule 19. The findings demonstrated that compound 19 had an IC₅₀ of 0.4 μM, making it a strong EGFR inhibitor. Compound 19 was the most potent COX-2 inhibitor and displayed higher potency against COX-2 (IC₅₀ = 0.46 μM) than against COX-1 (IC₅₀ = 30.41 μM) with an SI of 66.11. There was strong agreement between the observed biological results and molecular docking studies in the catalytic binding pocket of both protein receptors, EGFR and COX-2. Compound 19 was found to have acceptable physicochemical qualities and a decent drug-likeness based on the parameters of Veber's standard and Lipinski's rule of five.¹⁶⁰

Continuing the search for effective anticancer scaffolds, Shaker et al.¹⁶¹ reported the design synthesis and investigation of 1,3-diaryl pyrazole derivatives bearing a methyl sulfonyl moiety as potential anti-inflammatory and anticancer agents. The results of the MTT assay revealed that compound 20 (Table 1) was the most potent antiproliferative agent, with IC₅₀ values of 11.47, 8.45, and 6.77 μM against HepG-2, HCT-116, and MCF-7, respectively. Further evaluation of compound 20 on human embryonic kidney (HEK 293T) cells was performed to determine its safety against non-cancer cells. Compound 20 showed an IC₅₀ value of 37.07 μM, considering it nontoxic to normal cells. It displayed notable inhibition activity against both COX isoforms compared to the standard drugs indomethacin and celecoxib with enhanced activity against the COX-2 enzyme with IC₅₀ = 0.069 μM and SI = 159.4. Through the regulation of the G1 and S stages of the cell cycle, compound 20 caused MCF-7 cells to undergo cell cycle arrest and apoptosis. Additionally, docking and MD simulation results were consistent with in vitro COX-1/2 assays and clarified the reasons for the synthesized compounds' selectivity to the COX-2 enzyme.

Extending the theme of scaffold diversification, several 5- or 6- and N-substituted benzoxazole-2-carboxamide derivatives were designed, synthesized, and tested for their COX inhibitory and antiproliferative properties against MCF-7 and MDA-MB-231 cell lines to develop strong anticancer candidates. Compound 21 (Table 1), which is 5-methoxy and N-piperidine substituted, exhibited a modest inhibitory impact on the COX-1 (41.52%) and COX-2 (50.26%) enzymes. Regarding anticancer potential, compound 21 (IC₅₀ = 5.35 μM) exhibited comparable action to reference drug 5-FU (IC₅₀ = 3.95 μM) on MCF-7 cells, but a less harmful effect on the healthy WI-38 cell line (IC₅₀ = 19.04 μM). Compound 21 demonstrated selectivity that was almost 1.5 times greater for the MCF-7 cell line than the 5-FU control. It showed significant anticancer activity against the MDA-MB-231 cancer cell line with an IC₅₀ value of 11.02 μM. The effect of compound 21 on the cell cycle of the MCF-7 cell line was determined by flow cytometry. The results revealed that compound 21 increased the early stages of the apoptotic death process compared with the control group and significantly induced G0/G1 phase cell cycle arrest.¹⁶²

Furthermore, Abdelhaleem et al.¹⁶³ reported the design, synthesis, and biological evaluation of celecoxib analogs as apoptosis inducers and COX-2 inhibitors. The human breast cancer (MCF-7) cell line was used to test the antiproliferative activity of the newly synthesized celecoxib analogs in vitro by adopting the MTT assay, with celecoxib as a positive control. Compound 22 (Table 1) (IC₅₀ = 4.85 μM) showed 3.17-fold more potent anticancer activity than celecoxib. Compound 22 was chosen to conduct additional research to examine its impact on the advancement of the cell cycle and the activation of apoptosis in the MCF-7 cell line. Compound 22 induced an increase in the percentage of the cells at the S phase by 1.2-fold. The presence of a sub-G1 peak in the cell cycle profile of 22 confirmed the accumulation of the cells in the pre-G1 phase indicating a potential role of apoptosis in the mechanistic pathway of the antiproliferative activity of this compound. When MCF-7 cells were exposed to compound 22 at its IC₅₀ concentration for 24 hours, the tumor suppressor gene p53 and the proapoptotic protein Bax were markedly elevated, and BCL-2 was subsequently down-regulated in comparison with the control, demonstrating the compound's capacity to cause MCF-7 cells to undergo apoptosis. With an IC₅₀ value of 0.54 μM, compound 22 exhibited significant COX-2 inhibitory activity. The docking results revealed that celecoxib analog 22 fits on the COX-2 enzyme's active site, explaining its strong COX-2 inhibitory effect.

Complementing the previous study, the same research group developed celecoxib analogs with potential cytotoxic and pro-apoptotic activity against breast cancer cell line MCF-7. The most powerful anti-proliferative effect (IC₅₀ = 7.75 μM) was demonstrated by celecoxib analog 23 (Table 1). Its capacity to inhibit BCL-2 appears to be closely linked to its anti-proliferative action. Additionally, cell cycle arrest at the G2/M phase and cell accumulation in the pre-G1 phase result from activation of the DNA damage response system, suggesting that cell death occurs via an apoptotic mechanism. Through the activation of the intrinsic mitochondrial route of apoptosis, compound 23 demonstrated a strong pro-apoptotic activity. Significant increases in the expression of the tumor suppressor gene p53, the Bax/BCL-2 ratio, and the amount of active caspase-7 demonstrated this molecular route. Additionally, compound 23 exhibited a moderate inhibitory effect on COX-2 (IC₅₀ = 17.58 μM).¹⁶⁴

Adding to the growing body of evidence supporting hybrid frameworks, Al-Ghulikah et al.¹⁶⁵ repeated the design and synthesis of two series of cyanopyrimidine hybrids. With IC₅₀ values in the sub-micromolar range, all synthesized compounds showed strong activity at low concentrations when their COX-2 inhibitory activities were assessed. With the highest COX-2 percent inhibition (76.14%) and an IC₅₀ value of 0.16 μM, which is about equivalent to celecoxib and 10.5 times more than nimesulide, compound 24 (Table 1) was found to be the most active pyrimidine derivative. In addition, adopting the MTT assay, the pyrimidine derivative 24 showed modest cytotoxicity to the normal W38-I cell line and anticancer activity that was comparable or superior to doxorubicin against four cell lines: MCF-7, A549, A498, and HepG2. Its IC₅₀ values were in the nanomolar range (1, 1, 2, and 9 nM, respectively). Investigations into compound 24's impact on cell cycle progression and apoptosis induction revealed that it could stop cell growth at the sub-G1 and G2/M phases and raise the percentage of early and late apoptotic rates in MCF-7 cells by approximately 13 and 60 times, respectively. Compound 24's in silico tests showed encouraging results, including high GIT absorption, no BBB permeability, zero to low drug–drug interactions, good oral bioavailability, and ideal physicochemical characteristics, suggesting that it is a promising therapeutic candidate.

Continuing the scaffold diversification theme, Musa et al.¹⁶⁶ reported the synthesis and biological evaluation of chalcones as EGFR and COX-2 dual inhibitors. The synthesized chalcones were screened for cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375), and pancreatic cancer (PaCa-2) cell lines by adopting the MTT assay. Compound 25 (Table 1) exhibited potent EGFR inhibition with an IC₅₀ value of 0.8 μM. Additionally, it displayed great COX-2 inhibition with an IC₅₀ value of 1.27 μM. Interestingly, compound 25 exhibited the strongest cytotoxic effect with IC₅₀ values of 1.8, 1.2, 1.2, 3.2, and 2.1 μM, respectively, against Panc-1, H-460, HT-29, A375, and PaCa-2 cells. A virtual docking study of the compound under investigation with the receptor sites of EGFR and COX-2 rationalized its promising activity.

In the same direction, different 2-thioxoimidazolidin-4-one derivatives were synthesized. Using the neutral red uptake test, the cytotoxicity activity of the synthetic compounds was investigated as anticancer drugs against three cancer cell lines (A549, MCF7, and HepG2). Compound 26 (Table 1) showed moderate antiproliferative activity with IC₅₀ values of 74.64, 18.75, and 84.29 μM against A549, MCF7, and HepG2 cancer cell lines, respectively. Additionally, the QRT-PCR method was used to examine the COX-2 gene's expression level. Furthermore, when compared to control values, these results may show that compound 26 has potential effects on lowering drug resistance by downregulating the COX-2 gene when MCF-7 cells are used. These biological results were confirmed through molecular docking.¹⁶⁷

To deepen the exploration of the pyrazole motif in the design of potent COX-2 inhibitors, pyrazole derivatives with different substitutions were synthesized, and their anticancer potential was assessed by adopting the MTT assay. All the synthesized derivatives specifically inhibited the COX-2 enzyme (IC₅₀ = 0.043–0.56 μM). Methane sulfonyl derivative 27 (Table 1) was the most potent COX-2 inhibitor (IC₅₀ = 0.043 μM), displaying superior COX-2 selectivity (SI = 281.16) to celecoxib. Using doxorubicin and 5-FU as reference drugs, the most potent derivatives were tested for their antiproliferative efficacy against MCF-7 and HT-29 cancer cell lines. Compound 27 outperformed 5-FU against HT-29 cells and demonstrated superior cytotoxicity against MCF-7 (IC₅₀ = 2.85 μM) and HT-29 (IC₅₀ = 2.12 μM) cancer cell lines. It was a safe cytotoxic agent, as evidenced by its high IC₅₀ value of 115.75 μM against non-cancerous WI-38 cells. In HT-29 cells, it resulted in cell cycle arrest at the G1/S phase, which increased the number of early and late apoptotic stages and generated a buildup of cells in the G0 phase. Up-regulation of Bax, down-regulation of BCL-2, and activation of caspase-3/9 protein levels demonstrated apoptotic induction. Compound 27 decreased the levels of both total and phosphorylated EGFR in HT-29 cells and inhibited the EGFR (IC₅₀ = 0.083 μM) and Topo-1 (IC₅₀ = 0.020 μM) enzymes. A molecular docking investigation revealed strong binding interactions between compound 27 and target receptors, indicating its mechanism of action.¹⁶⁸

Continuing along similar lines, Kuran et al.¹⁶⁹ reported the design, synthesis, and pharmacological assessment of new thiosemicarbazone compounds, including tetralone and indanone, which selectively inhibit COX-2 as anticancer candidates. Studies of cytotoxic activity against the CCD-19Lu fibroblast cell line and A549 lung cancer cells were conducted by adopting the MTT method. Additionally, cytotoxic effects against HEK 293 immortalized human embryonic kidney cell lines and MCF-7 human breast cancer cell lines, COX-1 and COX-2 enzyme inhibitory activities, mitochondrial membrane potential (JC1), and caspase-3 activities were assessed by flow cytometric analysis. With an IC₅₀ value of 4.53 μM, compound 28 (Table 1) had the maximum cytotoxic effect against A549 lung adenocarcinoma cells. It was also less harmful to CCD-19Lu fibroblast cells, which are not malignant (IC₅₀ = 182.5 μM). It demonstrated selective COX-2 inhibition (IC₅₀ = 8.86 μM). Flow cytometric analysis revealed that compound 28 significantly induced apoptosis in A549 cells, with increased early and late apoptotic cell populations compared to untreated controls. Strong binding interactions between compound 28 and the COX-2 active site were shown by docking experiments, confirming the mechanism of selective inhibition. It induced caspase-3 activation on A549 cells compared to the control.

To develop new compounds with anti-inflammatory and anticancer properties, a series of bis-triazoles were synthesized. Compound 29 (Table 1) exhibited COX-2 inhibition with an IC₅₀ value of 0.363 μM and an SI of 12.67 compared to celecoxib (SI = 21.10). Adopting the MTT assay, it demonstrated significant antiproliferative potential with IC₅₀ values of 9, 12, 8, 3.3, and 16.5 μM against MCF-7, HEP-3B, HCT-116, A549, and F180 cell lines. Compound 29 inhibited aromatase (IC₅₀ of 30.30 μM), EGFR (IC₅₀ of 0.066 μM), and B-RAFV600E (IC₅₀ of 0.05 μM) enzymes. Treating MCF-7 breast cells with compound 29 resulted in cell cycle arrest at the G0–G1 phase and induction of apoptosis. The molecular modeling study rationalized the in vitro activity of this compound.¹⁷⁰

Broadening the search for celecoxib analogs as potent COX-2 inhibitors, Fadaly et al.¹⁷¹ reported the design and synthesis of pyrazolyl-thiazolidinone/thiazole derivatives as celecoxib/dasatinib analogs with selective COX-2, HER-2, and EGFR inhibitory effects. The synthesized derivatives were evaluated in vitro for COX-1/COX-2 inhibition, anticancer activity on MCF-7, A549, and F180 cell lines, and the mechanistic study of EGFR and HER-2 enzyme inhibition. Compound 30 (Table 1) showed potent COX-2 inhibition with an IC₅₀ value of 0.349 μM and an SI of 134.6, significantly higher than celecoxib's SI of 24.09. Regarding antiproliferative activity, adopting the MTT assay, it revealed potential activity against MCF-7 (breast cancer) cells (IC₅₀ = 0.73 μM), more potent than dasatinib (IC₅₀ = 7.99 μM) and doxorubicin (IC₅₀ = 3.1 μM). It showed prominent activity against A549 (lung cancer) cells (IC₅₀ = 1.64 μM), outperforming dasatinib (IC₅₀ = 11.8 μM) and doxorubicin (IC₅₀ = 2.42 μM). Derivative 30 inhibited EGFR and HER-2 with IC₅₀ values of 0.043 and 0.032 μM, respectively. The molecular modeling study explained this compound's in vitro activities.

Furthermore, Hosseini Nasab et al.¹⁷² reported the design and synthesis of thiazolyl-pyrazoline derivatives. The synthesized derivatives were evaluated for their in vitro anti-proliferative activities against human lung carcinoma (A549) and human melanoma cancer (A375) cell lines through the MTT assay. Compound 31 (Table 1) was recognized as the most potent derivative against both cell lines with IC₅₀ = 20.28 μM in A549 and 16.08 μM in A375. The results of the cytotoxicity revealed the selectivity of compound 31 towards cancer cells rather than normal rabbit articular chondrocytes (IC₅₀ = 145.5 μM). It was selected to be investigated for its anti-metastasis and anti-inflammatory properties via inhibition of the expression of matrix MMP-2 and 9 and COX-2. In A549 and A375 cells, upon exposure to compound 31, COX-2 expression was decreased. Molecular docking studies were carried out to show the possible interactions of synthesized compounds with the predicted active site of the COX-2 protein. The results revealed that compound 31 can bind well to the active site of the COX-2 protein.

Continuing with the scaffold diversification theme and using a one-pot double Mannich-type reaction, two series of chiral novel compounds were designed and synthesized. The central heterocyclic scaffold consisted of pyrimidine, purine, and purine bioisosteres, and the central core was either a purine nucleus with two vicinal phenyl and various heteroaryl moieties or a methylamino chain with a linear core. All the developed compounds were evaluated for anticancer testing against 60 different human cancer cell lines by the NCI (USA). Compound 32 (Table 1) demonstrated strong antitumor activity against a wide range of cancers, with a mean growth inhibition of 59.61%. It showed the highest anticancer activity against breast cancer cell lines MCF-7 (94.62%) and MDA-MB-468 (85.81%). Interestingly, almost all leukemia cell lines were sensitive to compound 32. Besides, it was potent against all colon, ovarian, and prostate cancer cell lines. Additionally, the IC₅₀ values of compound 32 against the most sensitive leukemia (HL-60 (TB)), ovarian cancer (SK-OV-3), and breast carcinoma (MCF-7) cell lines were determined to be IC₅₀ = 11.96, 9.46, and 6.68 μM. Compound 32 exhibited strong antiproliferative activity that was nearly comparable to or half that of doxorubicin (IC₅₀ = 12.54, 7.7, and 3.34 μM) and about 2- and 3-fold better than 5-FU (IC₅₀ = 19.99, 21.8, and 16.79 μM). It exhibited selective toxicity against cancer cells and minimal activity on the normal African green monkey kidney epithelial (Vero) cell line (IC₅₀ = 50.79 μM). A COX-2 inhibition assay assessed the target compounds' ability to inhibit COX-2. Compound 32 with an IC₅₀ value of 69.79 nM displayed interesting COX-2 inhibition activity in comparison with celecoxib (IC₅₀ = 53.76 nM). Further, compound 32 was able to arrest cell growth at the S and G2/M phases, indicating apoptosis induction. Additionally, it demonstrated a strong affinity for the COX-2 receptor through molecular docking. Additionally, in silico studies showed physicochemical characteristics, a strong pharmacokinetic profile, and drug-likeness data that were almost the same as those of celecoxib.¹⁷³

In the same direction, Hawash et al.¹⁷⁴ reported the design, synthesis, and biological evaluation of new thiazole carboxamide derivatives as anticancer agents and COX inhibitors. Cytotoxicity was assessed using an MTT assay against a cancer panel and normal cell lines. With IC₅₀ values of 30.79 μM and 74.15 μM, respectively, compound 33 (Table 1) showed anticancer activity against Colo205 and B16F1 cancer cell lines. IC₅₀ values of 203.71 μM against LX-2 cells and 116.96 μM against Hek293t cells demonstrated negligible cytotoxicity to normal cell lines, suggesting a strong therapeutic index. Compound 33 was identified as the most potent COX-2 inhibitor, exhibiting the lowest IC₅₀ value of 0.191 μM, with SI for COX-2 over COX-1. The pattern of ligand–protein interaction and orientations inside the binding site of COX-1 and COX-2 isozymes were examined using molecular docking studies, which helped to explain the COX-2 selectivity over COX-1 observed for the synthesized thiazole derivatives.

Continuing along similar lines, pyrimidine-5-carbonitrile derivatives were developed and tested for cytotoxic potential as dual EGFR^WT/COX-2 inhibitors. The biological evaluation showed that with an IC₅₀ value of 1.66 μM, compound 34 (Table 1) exhibited the strongest cytotoxic action across the NCI60 cancer cell line panel, especially against Colo 205 cells. This substance led to G1 phase cell cycle arrest and markedly increased apoptosis by a 10-fold rise in caspase-3 levels. Crucially, normal epithelial colon cells were shown to be unaffected by it (IC₅₀ = 46.34 μM). In comparison with erlotinib (IC₅₀ = 0.03 μM), compound 34 has been assessed for its inhibitory effect against EGFR^WT (IC₅₀ = 0.096 μM). Furthermore, compared to celecoxib (IC₅₀ = 2.59 μM, SI = 8.20), compound 34 demonstrated selective inhibitory action against COX-2 in vitro (IC₅₀ = 1.28 μM, SI = 8.55). According to molecular docking studies, 34 binds to the EGFR^WT/COX-2 active sites in an efficient manner that is like how common inhibitors like celecoxib and erlotinib bind. Additionally, positive drug-likeness characteristics were validated by SwissADME analysis, indicating that it may be used as a dual inhibitor in cancer treatment.¹⁷⁵

To further investigate the pyrazole motif in the development of potent COX-2 inhibitors, Fadaly et al.¹⁷⁶ reported the design, synthesis, modeling, and biological assessment of pyrazole compounds with oxime and nitrate moieties as selective COX-2 and aromatase inhibitors that have anti-inflammatory and anti-neoplastic properties with nitric oxide donation. Among the compounds evaluated using the MTT assay, compound 35 (Table 1) had the strongest anticancer activity, with IC₅₀ values against ovarian (IGROV1), breast (MCF-7), and melanoma (SK-MEL-5) cell lines of 3.12 μM, 4.28 μM, and 4.13 μM, respectively. Compound 35 displayed 4.82-fold selectivity towards MCF-7 compared to F180 fibroblasts. It caused cell proliferation to be inhibited and apoptosis to rise by inducing cell cycle arrest at the G2/M phase. With an IC₅₀ of 0.23 μM and an SI of 22.52, compound 35 additionally showed selective COX-2 inhibition. It also showed strong aromatase inhibitory activity (IC₅₀ = 16.50 μM), which was like letrozole, and slowly produced nitric oxide, which added to its anti-inflammatory and anticancer properties.

Adding to the growing body of data in favor of hybrid frameworks, a new series of linker-based NSAID derivatives were designed and synthesized. The synthesized compounds were evaluated for their antiproliferative and anti-inflammatory potential. Using the MTT assay, compound 36 (Table 1) showed the maximum cytotoxic activity against the MCF-7 breast cancer cell line in the investigation, with an IC₅₀ of 93.03 μg mL⁻¹. With an IC₅₀ value of 63.45 μg mL⁻¹, it also demonstrated considerable COX-2 inhibition, surpassing that of the reference drug ibuprofen. Compound 36 demonstrated dose-dependent suppression of cancer cell growth and induced apoptosis. Its robust binding contacts with COX-2 and HER-2 target sites were demonstrated by molecular docking and dynamics simulations, which added to its high bioactivity.¹⁷⁷

Building on the strategy of multitarget inhibition, Kothayer et al.¹⁷⁸ reported novel quinazolinone tethered phenyl urea derivatives that triple target the double mutant EGFR^L858R/T790M, COX-2, and 15-LOX. Using 60 distinct human tumor cell lines, the NCI (USA) screened the newly synthesized compounds for anticancer potential. With a growth inhibition percentage of 70.07%, compound 37 (Table 1) showed the strongest anticancer effect against the BT-459 breast cancer cell line. Additionally, it demonstrated low micromolar IC₅₀ values and significant COX-2 inhibition (IC₅₀ = 5.04 μM, SI of 5.34). Compound 37 demonstrated significant 15-LOX inhibition with an IC₅₀ value of 1.95 μM. Compound 37 showed micromolar anti-EGFR activity (IC₅₀ = 4.03 μM, SI > 24.8) against the double mutant EGFR^L858R/T790M. Molecular docking studies, which determine the target compounds' capacity to form critical interactions known to be crucial for EGFR, COX-2, and 15-LOX inhibitors, were used to supplement these findings.

Keeping with the concept of scaffold diversification, Bayanati et al.¹⁷⁹ reported the design and synthesis of benzo[4,5]imidazo[1,2-a]pyrimidine derivatives as selective COX-2 Inhibitors. The synthesized compounds were evaluated for anticancer potential against MCF-7 breast cancer cells by adopting the MTT method. The COX-2 inhibitory effects were also evaluated. All synthesized derivatives demonstrated moderate to good selectivity for COX-2 enzyme inhibition. Compound 38 (Table 1) demonstrated the strongest COX-2 inhibitory activity (IC₅₀ = 0.05 μM and SI = 122), surpassing the reference medication celecoxib's IC₅₀ value of 0.06 μM. It induced 53.33% growth inhibition of MCF-7 breast cancer cells at 10 μM concentration. Molecular modeling studies were performed, and the results revealed that the methyl sulfonyl pharmacophore was adequately placed into the COX-2 active site.

Likewise, Mekhlef et al.¹⁸⁰ reported the design and synthesis of 2,3-diaryl-1,3-thiazolidin-4-one derivatives, which were evaluated for their COX inhibitory activities and cytotoxicity against HePG-2, HCT-116, MCF-7, and PC-3 cancer cell lines using the MTT assay. With an IC₅₀ value of 0.06 μM and an SI of 204, compound 39 (Table 1) had the strongest inhibitory activity against COX-2, demonstrating potency and good selectivity in inhibiting the COX-2 enzyme. With IC₅₀ values of 2.31, 3.81, and 10.07 μM, compound 39 demonstrated the most potent cytotoxicity against HePG-2, MCF-7, and HCT-116 cancer cells. Mechanistic investigations demonstrated that compound 39 triggered apoptosis and caused cell cycle arrest during the G1 phase in HePG-2 cancer cells. The results of the in vitro COX-2 inhibition assay were in good agreement with the docking studies of compound 39 into the COX-2 active site.

In a related strategy, xanthene and thioxanthene analogs have been synthesized and investigated for their potential as anticancer agents and COX-2 inhibitors. The anticancer activities were tested against different cancer cell lines, including HeLa cells, hepatic cancer cells (Hep G2), and colon cancer (Caco-2) cells by adopting the MTS method. Compound 40 (Table 1) with an IC₅₀ value of 9.6 nM, demonstrated excellent antiproliferative activity against colon cancer cells (Caco-2). Compound 40 demonstrated potent COX-2 inhibition with an IC₅₀ value of 7.69 nM and high selectivity for COX-2 (SI 1.67).¹⁸¹

Expanding on the exploration of dual anticancer and anti-inflammatory potential of pyrazole derivatives, Yang et al.¹⁸² reported the design and synthesis of a series of 1,3-diaryl pyrazolyl ester derivatives. The synthesized derivatives were evaluated for their COX-2 inhibitory activity and anti-proliferation against HeLa (human cervical cancer) cells, MCF-7 (human breast cancer) cells, and MB-MDA-231 (human triple-negative breast cancer) cells via the MTT method. With an IC₅₀ value of 0.17 μM and an SI of 181, derivative 41 (Table 1) demonstrated a strong inhibitory effect on COX-2, suggesting great potency in inhibiting COX-2 activity. Compound 41's potential as an anticancer agent was highlighted by its notable antiproliferative effects on a variety of cancer cell lines, with GI₅₀ values of 4.61 μM for HeLa cells, 10.81 μM for MCF-7 cells, and 2.09 μM for MB-MDA-231 cells. Compound 41 demonstrated its capacity to inhibit cancer cell growth and encourage programmed cell death by inducing apoptosis and causing cell cycle arrest at the G2/M phase in MB-MDA-231 cells in dose-dependent and time-dependent manners. Additionally, molecular docking simulation rationalized the significant in vitro COX-2 inhibition of compound 41.

Likewise, derivatives of 3-(4-methylsulfonylphenyl) pyrazoles were designed, synthesized, and studied as possible anticancer candidates through the suppression of the enzymes cyclin-dependent kinase-2 (CDK2) and COX-2. Hepatocellular carcinoma (HepG-2), mammary gland breast cancer (MCF-7), and colorectal carcinoma (HCT-116) cell line panels were used to screen the synthesized compounds adopting the MTT assay. Compound 42 (Table 1) exhibited a significant antiproliferative effect on HepG-2, HCT-116, and MCF-7 cancerous cell lines with IC₅₀ values of 3.98, 8.70, and 7.85 μM. With an IC₅₀ value of 0.614 μM against the CDK2 enzyme, compound 42 demonstrated substantial inhibitory efficacy in comparison with the reference drug R-roscovitine (IC₅₀ = 0.533 μM). In contrast to celecoxib and indomethacin, which had COX-2 IC₅₀ values of 0.046 and 0.079 μM and SIs of 315.21 and 1.25, respectively, compound 42 demonstrated strong COX-2 inhibitory activity with an IC₅₀ value of 0.075 μM and an SI of 154.66. Compound 42 caused G1 phase cell cycle arrest in HepG-2 cancer cells, demonstrating apoptotic activity. Additionally, compound 42 dramatically increased the Bax/BCL-2 ratio, which is associated with its susceptibility to apoptosis, by 14.54 times when compared to the untreated reference. Strong binding affinities were found within the CDK2 and COX-2 active sites, as demonstrated by molecular docking and dynamics simulations used to depict the binding modes inside the active sites.¹⁸³

Continuing the exploration of selective COX-2 inhibitors, Huang et al.¹⁸⁴ reported the development of a series of 10-pterostilbene derivatives. The synthesized compounds were evaluated for their anticancer properties toward HepG2, Eac-109, and MDA-MB-231 cell lines in vitro using the MTT assay. When tested against cancer cells, the majority of derivatives showed considerable cytotoxicity, with IC₅₀ values ranging from 4.13 to 36.77 μM L⁻¹. They were less toxic to healthy human liver cells than cisplatin. Compound 43 (Table 1), with IC₅₀ values of 4.13, 5.99, and 7.68 μM L⁻¹ against HepG2, Eac-109, and MDA-MB-231 cells, demonstrated anticancer potential comparable to cisplatin on all tested cancer cell lines. The most promising COX-2 inhibitor was found to be compound 43 (IC₅₀ = 69.92 nm L⁻¹), which also demonstrated a strong Topo I inhibitory effect at 20 μM L⁻¹. Compound 43 caused major apoptosis in HepG2 cells by inducing reactive oxygen species (ROS)-mediated mitochondrial malfunction and changing the expression of apoptosis-related proteins like BCL-2, Bax, caspase 3/9, and P53, decreased the amount of CDK4 or cyclin D1, and significantly up-regulated P21. Additionally, it triggered G1 phase arrest on the HepG2 cancer cell line. Compound 43 effectively docked to COX-2 and Topo I protein with high affinities rationalizing the observed in vitro activity.

Further insights were taken from Hawash et al.¹⁸⁵ who reported the design and synthesis of a series of isoxazole-carboxamide derivatives. The synthesized derivatives were evaluated for COX inhibition and anticancer potential against CaCo-2, Hep3B, and HeLa cancer cell lines using the MTS assay. With IC₅₀ values ranging from 4.1 nM to 3.87 μM, all of the synthesized compounds demonstrated strong inhibitory effects against both COX enzymes. With IC₅₀ values between 0.24 and 1.30 μM and COX-2 SIs between 2.51 and 6.13, the results demonstrated that several compounds had strong COX-2 isozyme inhibitory actions. Of them, compound 44 (Table 1) had the lowest IC₅₀ value (0.247 μM) against COX-2, with a SI of about 4. With IC₅₀ values of 10.22, 4.84, and 1.57 μM, respectively, against CaCo-2, Hep3B, and HeLa cancer cell lines, this compound showed intriguing antiproliferative actions that were almost identical to those of doxorubicin. Compound 44 exhibited less cytotoxic activity than doxorubicin on the normal cell lines LX-2 and Hek293t, with IC₅₀ values of 20.01 and 216.97 μM, respectively. Additionally, compound 44 suppressed the colonization of HeLa and HepG2 cells and induced apoptosis. Furthermore, the mechanism behind the compound's cytotoxic activity and apoptotic effect may be the activation of ROS formation. The results showed that 44 inhibited the ability of Hep3B and HeLa cancer cells to form spheroid structures in the 3D multicellular tumor spheroid model. Additionally, compound 44's molecular docking showed a strong affinity for the COX-2 enzyme.

Finally, a series of 1,5-diaryl pyrazole derivatives were designed, synthesized, and evaluated for COX-2 inhibition and anticancer activity. Compound 45 (Table 1) exhibited significant COX-2 inhibitory activity with an IC₅₀ value of 0.781 μM and an SI of 5.96. Using the MTT growth inhibition assay, the target compounds were assessed for in vitro anticancer action against the lung cancer cell line A549 and the liver cancer cell line HepG2. Compound 45 (IC₅₀ = 40.14 μM) exhibited moderate anticancer potential against A549 cells. Furthermore, the molecular docking of compound 45 revealed a high affinity for the COX-2 enzyme.¹⁸⁶

6. A comprehensive comparative analysis of the reviewed COX-2 inhibitors

Pyrazole and pyrazoline are privileged scaffolds for the design and synthesis of potent COX-2 inhibitors with marked anticancer efficacy. Fourteen compounds, for example, 1, 5, 6, 17, 27, 31, and 45, incorporate either a pyrazole or pyrazoline scaffold exhibiting potential anticancer activity and exceptional COX-2 selectivity. para-Sulfonyl substitutions (compounds 17, 20, 22, 23, and 45) enhanced both COX-2 selectivity and anticancer potential. Celecoxib analogs 22, 23, and 30 demonstrated potential cytotoxic and pro-apoptotic activities. Aminophosphonate compounds 5 and 6 showed potential anticancer activity and selective COX-2 inhibition. This class of compounds induced cell cycle arrest and apoptosis via mitochondrial pathways. Triazole-containing compounds 8 and 29 showed high promise as COX-2 inhibitors with potential antiproliferative activity. These derivatives proved to be multi-target inhibitors. They exerted their efficacy via inhibition of COX-2, 15-LOX, hCA XII, and aromatase enzymes. Furthermore, they resulted in cell cycle arrest and induction of apoptosis. para-Sulfonyl substitution in the triazole derivative 29 was favorable for the activity. Because of their multi-pathway targeting, selectivity for cancer cells, and strong enzyme inhibition, pyrimidine-based COX-2 inhibitors 3, 24, and 34 are unique. They are very adaptable to various substitutions (such as aryl, sulfonyl, or cyano groups), which enhances pharmacokinetic and target selectivity, enabling multi-targeted cancer therapy. In contrast to non-selective NSAIDs, COX-2 inhibitors are developed to specifically inhibit the COX-2 enzyme rather than the COX-1 enzyme, which reduce pain and inflammation while exerting fewer gastrointestinal side effects. Additionally, most of the reviewed COX-2 inhibitors revealed potential antiproliferative activity against various cancer cell lines while exerting low cytotoxicity against normal cells, indicating their safety and therapeutic index.

7. Conclusion and prospects

COX-2 has become a key target for cancer treatment since COX-2 overexpression is a key factor in the development of many cancers. Through COX-2 inhibition, NSAIDs may prevent the growth of malignancies. NSAIDs' chemo-preventive impact is also greatly influenced by COX-2-independent pathways. NSAIDs exhibited greater potential in the prevention and treatment of various cancers, either alone or in combination with other conventional therapies such as sorafenib, 5-FU, bleomycin, and irinotecan. Several synthesized COX-2 inhibitors have proved excellent anticancer potential via different mechanistic pathways. COX-2 inhibitors have acceptable side effects and are reasonably priced when compared to conventional cancer treatments. The FDA has approved celecoxib (COX-2 inhibitor) as a chemo-preventive treatment. COX-2 inhibition provides new, potent, safe, and inexpensive options for the treatment of cancer patients. Thus, this review provides insight into the mechanisms of involvement of COX-2 in the initiation, proliferation, invasion, and metastasis of cancer cells. Also, it provides the most recent developments in the aspect of COX-2 inhibitors as potential anticancer candidates. It demonstrated the different mechanistic pathways for their anticancer potential. The mechanisms of the anticancer potential of COX-2 inhibitors must be better understood to design the next generation of cancer treatment drugs. Researchers can develop novel COX-2 inhibitors that could be used as effective therapeutic options for the treatment and prevention of various human cancers by using molecular modeling, in silico QSAR approaches, and high-resolution 3D protein structures. The development of COX-2 inhibitors as anticancer candidates can be accelerated by the application of artificial intelligence techniques such as drug scaffold generation and drug binding affinity predictors, which, when combined with experimental validation, are expected to be the newest weapons in the fight against human cancers soon.

8. Future aspects of the development of COX-2 inhibitors as anticancer agents

Since COX-2 was initially identified as a possible therapeutic or preventive target in cancer, significant advances have been made, particularly in the comprehension of the connection between the activity of cancer and the enzyme. COX-2 inhibitors provide a more focused approach than conventional chemotherapeutics, which frequently have wide-ranging cytotoxic effects and cause significant adverse effects. COX-2 inhibitors can be used as adjuvants or maintenance therapy because of their anti-inflammatory qualities, which help to inhibit the tumor microenvironment. Furthermore, several COX-2 inhibitors have demonstrated synergistic benefits when paired with conventional chemotherapeutic drugs or kinase inhibitors, indicating that they may be incorporated into multimodal treatment regimens such as combination therapy. The positive impacts of the combination therapy include enhanced anti-tumor efficacy, overcoming drug resistance, tumor microenvironment change, tailored drug delivery strategies, and a positive safety profile.

To further enhance therapeutic results, dual or multitarget inhibitors that combine COX-2 activity with EGFR, HER2, or other oncogenic targets may be developed. While preclinical and early clinical trials of COX-2 inhibitors have shown promising results and were generally well tolerated when used in combination with other drugs, further studies are needed to confirm these findings and determine the effectiveness of COX-2 inhibitor treatments in routine clinical settings. Several significant obstacles must be overcome to maximize the potential benefits of COX-2 inhibitors over existing therapeutic approaches as anticancer drugs. Comprehensive biomarker studies, extensive mechanistic research, and large-scale clinical trials are required to completely comprehend the therapeutic potential and maximize the use of COX-2 inhibitors in conjunction with other modalities. To guarantee patient safety and maximize therapeutic results, it is crucial to monitor and manage possible side effects and drug interactions. Improving pharmacokinetic characteristics, increasing bioavailability, and reducing the cardiovascular concerns that have been connected to this class should be the main goals of future research. To reach the full therapeutic potential of COX-2 inhibitors that represent a promising avenue in anticancer therapy, more extensive multidisciplinary research involving clinical trials, pharmacology, and medicinal chemistry will be necessary.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

The author declares no conflicts of interest.

Acknowledgments

The author is thankful to the Faculty of Pharmacy, Cairo University.

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Recent advances in targeting COX-2 for cancer therapy: a review

Asmaa E Kassab

Abstract

1. Introduction

2. Inflammation and cancer

2.1. Eicosanoids

2.2. COX isoforms

2.3. The involvement of COX-2 in cancer and other disease pathways

2.3.1. The involvement of COX-2 in cancer via the PG-dependent pathway

2.3.2. The involvement of COX-2 in cancer via PG-independent pathways

2.3.2.1. Mutagenesis

2.3.2.2. Angiogenesis

2.3.2.3. Cell motility, invasiveness, and metastasis

2.3.2.4. Apoptosis

2.3.3. The involvement of COX-2 in the maintenance of CSC populations

3. COX-2 inhibitors as anticancer agents

4. The mechanistic pathways of anticancer potential of COX-2 inhibitors

5. The anticancer activity of COX-2 inhibitors

Table 1. COX-2 inhibitors with anticancer potential.

6. A comprehensive comparative analysis of the reviewed COX-2 inhibitors

7. Conclusion and prospects

8. Future aspects of the development of COX-2 inhibitors as anticancer agents

Data availability

Conflicts of interest

Acknowledgments

References

Associated Data

Data Availability Statement

ACTIONS

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RESOURCES

Cite

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PERMALINK

Recent advances in targeting COX-2 for cancer therapy: a review

Asmaa E Kassab

Abstract

1. Introduction

2. Inflammation and cancer

2.1. Eicosanoids

2.2. COX isoforms

2.3. The involvement of COX-2 in cancer and other disease pathways

2.3.1. The involvement of COX-2 in cancer via the PG-dependent pathway

2.3.2. The involvement of COX-2 in cancer via PG-independent pathways

2.3.2.1. Mutagenesis

2.3.2.2. Angiogenesis

2.3.2.3. Cell motility, invasiveness, and metastasis

2.3.2.4. Apoptosis

2.3.3. The involvement of COX-2 in the maintenance of CSC populations

3. COX-2 inhibitors as anticancer agents

4. The mechanistic pathways of anticancer potential of COX-2 inhibitors

5. The anticancer activity of COX-2 inhibitors

Table 1. COX-2 inhibitors with anticancer potential.

6. A comprehensive comparative analysis of the reviewed COX-2 inhibitors

7. Conclusion and prospects

8. Future aspects of the development of COX-2 inhibitors as anticancer agents

Data availability

Conflicts of interest

Acknowledgments

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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