Advances in antitumor effects of pterostilbene and its derivatives

ABSTRACT

Pterostilbene (PT) is a naturally occurring small molecule stilbenoid that has garnered significant attention due to its potential therapeutic effects in tumor diseases. In this review, we conducted a comprehensive analysis of the antitumor effects of PT and its derivatives on various cancer types, including colon, breast, liver, lung, and pancreatic cancers in recent 20 years. We have succinctly summarized the PT derivatives that exhibit superior anti-tumor efficacy compared to PT. Additionally, we reviewed the potential structure-activity relationship (SAR) rules and clinical application methods to establish a foundation for chemical modification and clinical utilization of stilbene compounds.

GRAPHICAL ABSTRACT

1. Introduction

Pterostilbene (PT) is a naturally derived small molecule, earning its name from its initial discovery in Pterocarpus marsupium heartwood. It can also be found in various plant sources including blueberries, grapes, and palmetto. Functioning as a botanical antitoxin, it exhibits protective properties against diverse external factors such as ultraviolet radiation and pathogenic invasions [1]. Based on reported experimental evidence, PT exhibits potential therapeutic effects in cancer prevention and treatment, inflammatory skin diseases, regulation of blood sugar and lipid levels, cardiovascular disease management, aging intervention, as well as enhancement of memory and cognition [2]. Cancer refers to a malignant tumor. According to the latest global cancer statistics report released by the International Agency for Research on Cancer (IARC), it is estimated that there will be approximately 28.4 million new cancer cases worldwide by 2040 [3]. Numerous studies have demonstrated the potential of PT to impede cancer cell growth and proliferation, induce apoptosis, and halt cancer progression [4–6]. In terms of safety, administration of PT at a dosage of 3,000 mg/(kg-d) in animals did not result in any significant toxic side effects [7]. Due to its remarkable biological activity and promising medicinal value, PT has emerged as a prominent focus in cancer therapy research.

PT (3, 5-dimethoxy-4’−hydroxy stilbene) is a representative member of the stilbene family, as depicted in Figure 1. Studies have shown that the stilbene structure exhibits notable antitumor effects. Combretastatins, a class of stilbenes, have been extracted from Combretum afrum (Eckl. & Zeyh.) Kuntze and include compounds such as A1–5, which feature a cis-configuration and have demonstrated anticancer properties. Compounds of this class have been considered in anticancer clinical trials, indicating their potential therapeutic value in oncology. Trans-resveratrol and other natural trans-stilbenoids, such as PT, are known for their outstanding antitumor effects; however, their clinical application is impeded by limited bioavailability, which hinders their broader use in medicine. Compared to resveratrol, the substitution of the two hydroxyl groups in the left ring with methoxy groups resulted in a significant enhancement of both bioactivity and bioavailability of PT. This discovery serves as a source of inspiration for us to modify the structure based on PT and systematically investigate the potential SAR, thereby facilitating the exploration of derivatives with enhanced research value and medicinal potential in future studies.

Figure 1.

Chemical structure of pterostilbene.

In this review, we present a comparative analysis of the pharmacodynamics and pharmacological effects of PT and its derivatives across various cancer types, encompassing colon, breast, liver, lung, and pancreatic cancers. In order to provide a comprehensive and systematic description of the antitumor effects of PT and its derivatives, we have carefully selected relevant references from the past two decades. Additionally, we discuss the SAR between PT and derivatives with various modified structures, thereby establishing a fundamental basis for the chemical modification and clinical application of stilbene compounds.

2. Colon cancer

Colon cancer is a prevalent gastrointestinal malignancy primarily affecting the colon region. Minimally invasive endoscopic procedures are effective in treating early-stage cases, while late-stage treatment necessitates a comprehensive approach encompassing surgery, chemotherapy, immunotherapy, traditional Chinese medicine, and other supportive therapies [8]. The inhibitory effects of PT on azoxymethane-induced colonic abnormal crypt foci (ACF) and colonic tumors have been demonstrated. Moreover, PT and its derivatives exhibit potent antitumor activity in colon cancer cell lines HT-29, Caco-2, and HCT116 by modulating the p38/MAPK pathway and PI3K/Akt pathway, as well as suppressing colon inflammation through inhibition of iNOS and COX-2 expression (Figure 2). These findings suggest that PT derivatives hold promise as potential therapeutic agents for inhibiting further progression of colon cancer.

Figure 2.

Schematic representation of antitumor effects of pterostilbene and its derivatives on colon cancer, breast cancer, liver cancer, lung cancer and pancreatic cancer.

2.1. PT against colon cancer

Excessive production of nitric oxide has been implicated in the pathogenesis of colonic mucosal and tissue damage, thus aggravating the inflammatory cascade. Consequently, efficacious management of colonic inflammation holds substantial potential for attenuating colon tumor progression. In 2007, Suh et al. discovered that PT effectively inhibits the formation of azoxymethane-induced ACF precancerous lesions in mice colon [9,10]. Mechanistic studies further revealed its inhibitory effects on colon tumors by down-regulating the expression of inflammation-inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) genes, as well as inducing apoptosis. Furthermore, in 2011, Chiou et al. demonstrated that PT attenuated the activation of nuclear factor-κB (NF-κB) by inhibiting the phosphorylation of protein kinase C-β2 (PKC-β2), subsequently resulting in a reduction in the expression of downstream target genes such as aldose reductase, iNOS, and COX-2. This mechanism hinders cellular inflammation and oxidative stress through the activation of NF-E2-related factor 2 (Nrf2) during azoxymethane-induced colon carcinogenesis [11].

PT effectively suppressed the proliferation of human colon cancer cells in vitro studies. Wawszczyk et al. observed a dose- and time-dependent reduction in the proliferation rate of Caco-2 and HT-29 cells upon treatment with PT, accompanied by a decrease in the number of G2/M phase cells and an up-regulation of p21 expression (Table 1). The antiproliferative and cytotoxic effects of PT were potent, potentially exerted through the regulation of the STAT3 and AKT kinase signaling pathways [12,13]. Furthermore, PT effectively suppressed colony formation in human colon cancer cells including Caco-2, HT-29, and HCT-116. The sensitivity to PT and resveratrol treatment varied among these cell lines with the highest response observed in Caco-2 followed by HT29 and HCT116; notably, PT exhibited superior inhibitory effects compared to resveratrol across all three cell types (IC50 values for PT: Caco-2: 75 µM; HT29: 15 µM; HCT116: 12 µM) [14,15]. Paul et al., in their study on HT-29 cells, demonstrated that PT effectively suppressed cell proliferation by down-regulating c-Myc expression and cyclin D1 levels, while simultaneously increasing cleaved PARP levels. Furthermore, PT exhibited inhibitory effects on iNOS and COX-2 expression through the regulation of the p38 mitogen-activated protein kinase (MAPK) pathway. Additionally, PT modulated detoxification enzyme levels such as glutathione transferase to enhance carcinogen excretion and prevent colon carcinogenesis [16–18].

Table 1.

PT and its derivatives in colon cancer cells: dose and effects.

Cancer type	Models	Compound	Dose	Anticancer Effect	Reference
Colon cancer	HT29 cells	Pterostilbene	0,5,10,25,40,50,60,75,100 µM(48,72 h)	Inhibition of proliferation, G1 cell arrest, and/or triggering apoptosis IC50 values of 45.1 ± 13.7 µM (48 h); 37.9 ± 5.4 µM (72 h)	[12]
			Unclear	IC50 values of : 10 ± 2 µM; Resveratrol :78 ± 4 µM	[22]
	Caco-2 cells	Pterostilbene	5–100 μM (48,72 h)	Significant dose-dependent antiproliferative and cytotoxic effects IC50 values of 67.6 ± 12.3 µM（48 h）; 43.0 ± 11.6 µM (72 h)	[15]
			0.78–100 μM(48,72 h)	IC50 values of 34.0 ± 8.1 μM (48 h);24.4 ± 11.3 μM (72 h)	[20]
	COLO205 cells		5–100 μM (24 h)	IC50 values of 9.0 ± 0.2，40.2 ± 0.6，70.9 ± 1.0; Pterostilbene: 33.4 ± 0.2，47.1 ± 0.6，80.6 ± 3.3（in COLO205、HCT-116和HT-29 cells）	[19]

2.2. PT derivatives against colon cancer

Cheng et al. discovered that 3’-hydroxypterostilbene exhibits potential anti-colon cancer properties. In nude mice bearing COLO205 tumor xenografts, intraperitoneal injection of 3’-hydroxypterostilbene (10 mg/kg i.p.) resulted in the down-regulation of COX-2, matrix metalloprotein peptidase-9 (MMP-9), vascular endothelial growth factor (VEGF), and cell cycle protein D1 levels. Meanwhile, 3’-hydroxypterostilbene exhibited superior IC50 values compared to PT in COLO205, HCT-116, and HT-29 cells (IC50 values for 3’-hydroxypterostilbene derivatives: 9.0 ± 0.2, 40.2 ± 0.6, 70.9 ± 1.0; PT: 33.4 ± 0.2, 47.1 ± 0.6, 80.6 ± 3.3). In COLO205 cells, 3’-hydroxypterostilbene was observed to decrease the phosphorylation of p38 MAPK and PI3K/Akt/mTOR/p70S6K while activating the ERK1/2 and JNK1/2 MAPK pathways in a time-dependent manner. The results of this study suggest that 3’-hydroxypterostilbene exhibits a higher potency in inducing autophagy compared to PT in COLO205 cells [19].

González-Sarrías et al. investigated the IC50 values of gut microbiota metabolites of PT in Caco-2 cells and observed that 4-hydroxystilbene, exhibiting the lowest IC50 value (Table 1), demonstrated superior antiproliferative activity compared to PT. Furthermore, it was discovered that the differential metabolizing ability of these compounds may account for PT’s heightened sensitivity toward Caco-2 cells as opposed to HT-29 cells [20].

Pinostilbene, the main metabolite of PT in the colon, was derived by Sun et al., who demonstrated that it induced S-phase cell cycle arrest at concentrations of 20 and 40 μM and significantly suppressed the growth of HT-29 and HCT-116 cells [21].

Grau et al. modified the stilbenes’ structure through alkylation or acylation of hydroxyl groups and assessed their IC50 values in HT-29 cells. The 2-arylindole analogue (Table 1) exhibited higher cytotoxicity compared to resveratrol (IC50 value of 10 ± 2; Resveratrol :78 ± 4), and its benzylated analogue possessed K-Ras inhibitory effects in HCT-116 colon cancer cells [22].

3. Breast cancer

Breast cancer is a prevalent malignancy in women, with its incidence rate steadily increasing over the years. Among the various types of breast cancer, triple-negative breast cancer is referred to as the “monarch” due to its unfavorable prognosis, heightened risk of distant metastasis, and substantial proportion of proliferating cancer cells. Currently, there are no established treatment guidelines for triple-negative breast cancer [23]. The PT and its derivatives exhibit promising potential as anti-breast cancer agents, demonstrating efficacy against triple-negative breast cancer cells, MCF-7 cells, and stem cells. Their primary mechanisms of action involve the modulation of key pathways including JAK/STAT3, wnt/β-linker, NF-κB/miR488, PI3K/Akt/mTOR signaling cascades, along with the regulation of genes associated with tumorigenesis (Figure 2).

3.1. PT against breast cancer

Among the various subtypes of human breast cancer cells, extensive research has been conducted on the anticancer efficacy of PT specifically in MCF-7 cells. It has been experimentally demonstrated that PT effectively induces apoptosis in MCF-7 cells. On one hand, PT upregulates mitochondrial apoptotic signals, such as Bax and a series of cysteine aspartic enzymes, thereby inducing cysteine aspartase-dependent apoptosis through increased activation of downstream effectors prompted by elevated superoxide anion levels and mitochondrial depolarization [24–26]. On the other hand, PT enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating the reactive oxygen species (ROS)-mediated CHOP pathway [26,27]. Additionally, PT has been shown to impede MCF-7 cell proliferation through the modulation of the wnt/β-linker pathway and suppress EMT- and HRG-β1-induced cellular invasion by downregulating Akt, Bcl-2, MMP-9, and lncRNA expression [28–30]. The clinical enhancement of PT’s anti-proliferative, pro-apoptotic, and oxidative potential in MCF-7 cells can be achieved through combination therapy with tamoxifen or by utilizing zein nanocomposites as carriers [31,32]. PT can also induce autophagy, which exhibits cytoprotective effects, thereby suggesting its potential clinical application in combination with autophagy inhibitors [29]. Chakraborty et al. reported that the growth arrest observed in MCF-7 cells might be linked to the induction of cellular autophagy and a transformation toward an epithelioid cell-like phenotype, as demonstrated by their study [33].

The proliferation and migration of triple-negative breast cancer cells were effectively inhibited by PT. Wakimoto et al. demonstrated the high sensitivity of PT in suppressing the growth of triple-negative breast cancer cells [34]. PT suppressed the proliferation of triple-negative breast cancer cell by inhibiting the expression of cMyc and human telomerase reverse transcriptase (hTERT) expression, down-regulating mutant p53, cell cycle protein D1, mammalian target of rapamycin (mTOR), and β-linker protein expression [35,36]. The underlying mechanism may involve the JAK/STAT3 signaling pathway [37]. Su et al. demonstrated the anti-metastatic potential of PT in vitro and in vivo by regulating EMT of triple-negative breast cancer cells through up-regulation of microRNA-205, possibly via modulation of the Src/Fak signaling pathway [38]. The activity of MMP-2 and MMP-9, as well as the migration of triple-negative breast cancer cells, were also suppressed by PT through inhibition of NF-κB-mediated expression of urokinase-type fibrinogen activator, invasive foot-related protein, and Rac1/WAVE-2/Arp2/3 pathway [39,40].

3.2. PT derivatives against breast cancer

Van den Brand et al. reported that 2,3‘,4,5’-tetramethoxy-trans-stilbene (Table 2) activated the aryl hydrocarbon receptor AHR (with an EC50 value of 2.0 μM) and induced AHR-mediated cytochrome P450 1A1 (CYP1A1) activity (with an EC50 value of 0.7 μM), while also exhibiting greater efficacy in reducing viability and migration of MCF-7 cells compared to PT and resveratrol. The derivative exhibited selective inhibition of the G1 phase in the MCF-7 tumor cell cycle, while leaving the cell cycle status unaffected in the non-tumorigenic epithelial cell line MCF-10A cells. Interestingly, this study represents a pioneering demonstration that this compound selectively targets breast cancer cells without impacting non-tumorigenic cells. Cell type-specific differences may arise due to variations in the AHR ligand binding pockets, distinct recruitment of co-activators/repressors, and cell-type specific expression patterns, as well as differential availability of ligand DNA recognition sites among the investigated cell lines [41].

Table 2.

PT and its derivatives in breast cancer cells: dose and effects.

Cancer type	Models	Compound	Dose	Anticancer Effect	Reference
Breast cancer	MCF-7 cells	Pterostilbene	0–150 μM (24,48,72 h)	Inhibition of Wnt signaling, cell cycle arrest and apoptosis	[29]
			0–30 μM (10 days)	Inhibition of cell activity and migration, cell cycle shift, activation of AHR and EROD activities IC50 values of 3.6 μM; PT: 15.6 μM	[41]
	Triple-Negative Breast Cancer Cells	Pterostilbene	Unclear	Inhibition of MDA-MB-231 cell proliferation and migration	[34,38]
			0–1000 μM (3 days)	High ratio of renilla luciferase and Wnt IC50 values (5.1 ± 0.6 μM)	[46]
	BCSC cells	Pterostilbene	Unclear	Inhibition of M2 tumor-associated macrophage (TAM)-induced BCSC proliferation and metastasis	[47]
			Unclear	Inhibition of mammosphere formation, reduction of BCSC markers such as acetaldehyde dehydrogenase (ALDH) and CD44 levels, and modulation of various stem cell maintenance pathways	[49,50]

The current focus in the field of epigenetic cancer research lies in addressing hypermethylation of tumor suppressor genes and hypomethylation of genes associated with cancer-promoting functions. Lubecka et al. have successfully identified, for the first time, a comprehensive genome-wide landscape responsive to resveratrol-induced DNA methylation. They demonstrated that stilbene compounds target key regulators of cancer signaling pathways and methylated genes associated with oncogenic and pro-metastatic functions, resulting in the epigenetic silencing of MAML2 and the subsequent inactivation of NOTCH signaling [42]. Subsequently, Beetch et al. conducted genome-wide DNA methylation analyses to investigate the modified response profile to stilbenes, revealing dynamic interactions between DNA and DNMT3A and NF1C transcription factors. Additionally, they elucidated the mechanism of DNMT3B-dependent hypermethylation and silencing of OCT1-targeted oncogenes. It was observed that PT derivatives could induce alterations in the epigenetic marks within the oncogene enhancer region of breast cancer cells [43–45]. These findings suggest that PT derivatives possess the potential to modulate epigenetic marks specifically in the oncogene enhancer region of breast cancer cells, thereby exerting inhibitory effects on breast cancer progression through gene targeting.

Huber et al. synthesized a total of 73 dimeric stilbene analogues through the biotransformation reaction of a mixture containing PT and resveratrol with the enzymatic secretome derived from the gray mold fungus. Interestingly, they identified several structurally distinct derivatives that exhibited specific inhibition of the Wnt pathway in triple-negative breast cancer cells (Table 2). It was observed that these derivatives effectively suppressed Wnt activity and impeded β-linker accumulation in both the cytoplasm and nucleus by disrupting nuclear effectors downstream of the disruption complex [46].

The proliferation and metastasis of breast tumor stem cells (BCSCs) induced by M2 tumor-associated macrophages (TAMs) can be effectively inhibited by PT through modulation of EMT-related signaling pathways, particularly the NF-κB/miR488 pathway [47]. Certain phytochemicals (Table 2), akin to PT, can also target BCSC and suppress tumors by inhibiting mammosphere formation, reducing levels of BCSC markers such as acetaldehyde dehydrogenase (ALDH) and CD44, and modulating various stem cell maintenance pathways [48–50].

4. Liver cancer

Liver cancer exhibits a high incidence and mortality rate, while its advanced treatment yields a low cure rate due to the dissemination of cancer cells [51]. PT has been shown to impede the proliferation and migration of liver cancer cells, induce apoptosis, and its derivatives can inhibit the growth of HepG2 cells. The main mechanisms involved in regulating these effects include modulation of the PTEN/Akt pathway and AMPK signaling pathway, as well as suppression of MAT1 expression and MMP-9 activity (Figure 2). These findings hold significant implications for liver cancer research.

4.1. PT against liver cancer

The proliferation of liver cancer cells was inhibited and apoptosis was induced by PT treatment. Guo et al. demonstrated that PT induced an elevation in reactive oxygen species (ROS) levels and triggered activation of the mitochondrial apoptotic pathway through upregulation of p53 expression and downregulation of superoxide dismutase 2 (SOD2) expression. This led to a dose-dependent inhibition of tumor growth in diethylnitrosamine plus carbon tetrachloride-induced hepatocellular carcinoma mice, as well as a dose-dependent reduction in viability of HepG2 cells. Furthermore, this treatment induced apoptosis without exhibiting genotoxic activity [52,53]. The Ribonucleotide reductase M2 (RRM2) protein plays a pivotal role in DNA synthesis and repair, thereby facilitating cellular proliferation while suppressing apoptosis. Wang et al. demonstrated that PT exhibited a potent inhibitory effect on the activity of RR enzyme in vitro through its specific targeting of RRM2 (with an IC50 value of approximately 0.62 μM). Notably, this inhibitory potency surpasses that of currently available drugs targeting RRM2 and warrants further clinical validation [54]. PT can enhance the expression of phosphatase and tensin homolog (PTEN) by downregulating miR-19a and activating the PTEN/Akt pathway. Moreover, it exerts inhibitory effects on cell proliferation and induces apoptosis in tumor cells by downregulating HDAC1 and HDAC2 while upregulating acetylated p53 [55–57]. Dewi et al. demonstrated that PT effectively suppresses the proliferation of AH109A cells by inducing cell cycle arrest at the G0/G1 phase, exhibiting a dose-dependent reduction in the expression of cyclin-dependent kinases 4/6 (CDK4/6), and elevating intracellular peroxide levels [58]. Furthermore, Lee et al. demonstrated that PT could effectively prevent the enrichment of CD133(+) liver cancer CSCs, suppress tumor sphere formation, and downregulate stemness gene expression [59].

PT exhibits inhibitory effects on the migration and invasion of liver cancer cells. Pan et al. demonstrated that PT effectively suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced migration in HepG2 cells by downregulating MMP-9 gene expression [60]. Qian et al. discovered that PT effectively suppressed motility and invasion in human liver cancer cells by down-regulating metastasis-associated protein 1 (MTA1) [56]. Furthermore, the combination of PT with curcumin and its analogues targeting lysyl oxidase demonstrated noteworthy antitumor metastatic activity, warranting further investigation [61]. Tzeng et al. revealed that under hypoxic conditions following catheter artery chemoembolization treatment, nanoparticles of PT exhibited enhanced cytotoxicity compared to PT alone. Moreover, these nanoparticles effectively suppressed the expression of hypoxia and apoptosis-associated proteins, thereby mitigating tumor invasion and metastasis [62].

4.2. PT derivatives against liver cancer

Hasiah et al. investigated the SAR between cytotoxicity and antioxidant activity of six methoxylated stilbene analogues in HepG2 cells, employing MTT assay for cytotoxicity evaluation and trivalent ferric reducing antioxidant power (FRAP) assay for measuring antioxidant activity. The concentration-dependent cytotoxicity and antioxidant activity of the stilbene analogues were observed, with (Z)-3,4,4’-trimethoxystilbene (Table 3) exhibiting the highest potency and selectivity as an antiproliferative agent in HepG2 cells (with an IC50 of 89 µM), while also demonstrating the most pronounced antioxidant activity across all concentrations [63]. The discovery of these findings presents novel perspectives for the investigation of PT derivatives.

Table 3.

PT and its derivatives in liver cancer cells: dose and effects.

Cancer type	Models	Compound	Dose	Anticancer Effect	Reference
Liver cancer	HepG2 cells	Pterostilbene	0,12.5,25,50,100 µM (24 h)	Concentration-dependent decrease in cell viability and proliferation	[53]
			3.125–100 µM (24 h)	Inhibited cell proliferation (IC50 values of 89 μM) with significant antioxidant activity at all concentrations	[63]

5. Lung cancer

Lung cancer is a malignancy characterized by a high global incidence and mortality rate. It encompasses two fundamental subtypes: small cell lung cancer (SCLC), which represents a minority of cases and is primarily managed through systemic chemotherapy in combination with radiotherapy and surgery; non-small cell lung cancer (NSCLC), comprising adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, predominantly treated using surgical interventions [64]. The PT and its derivatives exhibit promising inhibitory effects on lung disease-associated tumors both in vivo and in vitro. Their main mechanisms involve the regulation of the Notch1 signaling pathway, AKT and JNK pathways, as well as modulation of cell proliferation and apoptosis through P53 and COX-2 regulation (Figure 2). These findings highlight their potential as therapeutic agents for lung cancer, warranting further comprehensive investigations.

5.1. PT against lung cancer

Chen et al. demonstrated that PT significantly attenuated tumor heterogeneity, reduced tumor volume, and suppressed tumor burden in ethyl carbamate-induced lung tumors in mice by inhibiting the epidermal growth factor receptor (EGFR) and its downstream signaling pathways [65]. Furthermore, Ma et al. demonstrated that PT effectively suppressed tumor growth in PC9 ×enografts in thymus-free nude mice by activating the endoplasmic reticulum stress (ERS) signaling pathway and promoting apoptosis-related protein expression. Notably, these effects were synergistically enhanced by Mediterranean flavin [66]. Surien et al. found that PT significantly up-regulated p53, p21 and p27 protein expression as well as the p53/p21 pathway in an N-nitroso-trichloroethylurea (NTCU)-induced squamous cell carcinoma (SCC) Balb/C mouse model of the lung. This led to cell cycle arrest and inhibited the progression of precancerous lesions by reducing the thickness of bronchial epithelium [67,68].

PT has been demonstrated to induce cellular senescence and inhibit cell proliferation in lung cancer cells. Tippani et al. reported significant telomerase inhibition, anti-mitotic activity, and anti-proliferative effects of PT in NCI-H460 cells [69]. Chen et al. initially investigated this novel anticancer mechanism using telomerase-induced senescent cells of lung cancer and discovered that PT can effectively inhibit telomerase activity, induce the DNA damage response, and significantly decrease cell viability in a concentration- and time-dependent manner. Ultimately, it leads to cellular senescence through a p53-dependent pathway [70,71]. Lee et al. demonstrated the essential role of p53 in the mechanism of PT action. They observed that PT induced activation of ATM and CHK1/2 upstream of p53 in two precancerous human bronchial epithelial cell lines, HBECR and HBECR/p53i, leading to a more potent inhibition of cell cycle progression and p53-dependent cell proliferation [72]. Additionally, Huang et al. demonstrated that PT treatment resulted in the down-regulation of MUC1, NF-κB, CD133, β-catenin, and transcription factor SOX2 expression and exhibited a dose-dependent inhibition of CSC proliferation [73].

PT can induce apoptosis and autophagy in lung cancer cells. Hsieh et al. demonstrated that PT treatment induced autophagy through the inhibition of AKT and JNK pathways, as well as the activation of Extracellular regulated protein kinases 1/2 (ERK1/2). Moreover, their study revealed that pre-treatment combined with autophagy inhibitors, such as 3-methyladenine and bafilomycin A1, effectively enhanced apoptosis in docetaxel-induced multidrug-resistant human lung cancer cell lines [74]. Mena et al. discovered that lysosomal membrane permeabilization serves as the primary mechanism of cell death induced by PT. A375 melanoma and A549 lung cancer cells with low levels of HSP70 showed high susceptibility to PT, whereas HT29 colon and MCF7 breast cancer cells with higher levels of HSP70 were more resistant [75]. The presence of PT in NSCLC cells resulted in the augmentation of endoplasmic reticulum stress signals, namely PERK, IRE1, ATF4, and CHOP. Consequently, this led to an upregulation of ROS levels, a downregulation of intracellular glutathione levels, induction of apoptosis and inhibition of cell viability. This regulatory mechanism is potentially associated with COX-2 [66,76]. In human lung adenocarcinoma cells, PT modulated the apoptotic index and reactive oxygen species levels by regulating Notch1 signaling pathway transmission, mitochondrial membrane potential, and intracellular glutathione content [77].

5.2. PT derivatives against lung cancer

ivative 4,4’-(ethane-1,2-diyl) bis (2-methoxyphenol) (Table 4) exhibited a high-affinity interaction with an Akt molecule at both the ATP-binding and allosteric sites. Moreover, it significantly reduced cell viability (IC50 of 108.6 ± 10.82, 103.5 ± 6.08, and 138.3 ± 25.63 μM) and colony formation in NSCLC (A549, H23, and NCI-H460), suggesting its potential as an Akt inhibitor. The treatment also demonstrated a dose-dependent increase in the apoptosis rate of A549 cells, with percentages of 23.25%, 61.26%, and 86.30% observed at concentrations of 10, 100, and 200 μM, respectively [78].

Table 4.

PT and its derivatives in lung cancer cells: dose and effects.

Cancer type	Models	Compound	Dose	Anticancer Effect	Reference
Lung cancer	A549 Cells	Pterostilbene	Unclear	Regulated NSCLC cell proliferation and apoptosis via targeting COX-2	[66,76]
			0–200 µM (24 h)	Inhibited cell proliferation and induced apoptosis IC50 values of 108.6 ± 10.82; 103.5 ± 6.08; 138.3 ± 25.63 μM（in A549, H23, and H460 cells) Resveratrol :>200 μM	[78]
	PC9 cells	Pterostilbene	Unclear	Elimination of Osimertinib resistance	[123]
			0–500 µM(24,48 h,72 h)	IC50 values of 45.64 ± 2.06 µM(24 h);56.78 ± 1.97 µM(48 h);72.54 ± 3.25 µM (72 h;in PC-9cells);46.78 ± 1.87 µM(24 h);60.47 ± 2.87 µM(48 h);76.98 ± 2.58 µM(72 h;in H1299 cells)	[79]

Stilbenes exert an impact on gefitinib resistance in NSCLC cells. Lu et al. discovered that trans-3,5,4’-trimethoxystilbene (Table 4) effectively inhibited the MAPK/Akt/Bcl-2 pathway by upregulating the expression of miR-345 and miR-498, thereby enhancing sensitivity to gefitinib and inducing apoptosis [79].

6. Pancreatic cancer

Pancreatic cancer is considered one of the malignancies with the most unfavorable prognosis, characterized by insidious and atypical clinical manifestations. Its diagnosis and treatment pose significant challenges due to its complex tumor microenvironment. With a high surgical mortality rate and low cure rate, pancreatic cancer prevention and treatment hold immense clinical significance [80]. PT and its derivatives exhibit potent antiproliferative activity against pancreatic cancer by down-regulating the RAGE/STAT3 signaling pathway, rendering them promising candidates for intensive investigation as therapeutic agents in the management of this malignancy (Figure 2).

6.1. PT against pancreatic cancer

The Pancreatic Ductal Adenocarcinoma (PDAC) constitutes 80–90% of pancreatic malignancies and represents one of the most lethal neoplasms [81]. Hsu et al. demonstrated that PT effectively suppressed cell proliferation, induced apoptosis and autophagy, and down-regulated the expression of multidrug resistance protein 1 (MDR1) by targeting the RAGE/PI3K/Akt signaling pathway in PDAC cells, thereby enhancing chemical sensitivity [82]. Chen et al. discovered that PT could enhance anticancer effects in combination with the autophagy inhibitor chloroquine, as evidenced by their ability to down-regulate the RAGE/STAT3 signaling pathway and inhibit pancreatic cancer growth and tumor autophagy in an in-situ animal model [83].

The proliferation of the PANC-1 pancreatic cancer cell line was effectively inhibited by PT treatment. In the PANC-1 pancreatic cancer cell line, PT effectively suppressed mitochondrial membrane depolarization and activation of effector cysteine asparaginase, leading to a concentration- and time-dependent reduction in cell viability. Moreover, PT induced S-phase cell-cycle arrest, apoptosis, and autophagy [82,84]. Kostin et al. demonstrated a synergistic antiproliferative effect of PT in combination with epigallocatechin gallate (EGCG, Table 5) on the PANC-1 cell line [85]. The antiproliferative effect of PT was initially demonstrated by McCormack et al., who observed that PT modulated gene expression in PANC-1 cells, upregulated the antiproliferative markers cytochrome C, Smac/DIABLO, and MnSOD/antioxidant activity, and suppressed STAT3 phosphorylation. Furthermore, oral administration of PT effectively inhibited tumor growth [86].

Table 5.

PT and its derivatives in pancreatic cancer cells: dose and effects.

Cancer type	Models	Compound	Dose	Anticancer Effect	Reference
Pancreatic cancer	PDAC cells	Pterostilbene	0–75 μM (48,72 h)	Inducing S-phase cell cycle arrest, apoptosis, and autophagic cell death and inhibiting multidrug resistance protein 1 (MDR1) expression	[82,83]
			Unclear	IC50 values of 28 ± 4 µM; Resveratrol :132 ± 6 µM	[22]
	AsPC1, BxPC3, and Capan2 cells		0–100 μM(72 h)	IC50 values of 14.72 μM; 22.70 μM;27.75 μM; Resveratrol:29.01 μM;48.73μ; >100 μM (in AsPC1, BxPC3, and Capan2 cells)	[87]

6.2. PT derivatives against pancreatic cancer

Florio et al. demonstrated that the modified PT derivative (Table 5) exhibited enhanced efficacy in suppressing clonogenicity and inhibiting colony formation in pancreatic cancer cell lines, achieved by preserving the 4′-phenol moiety while introducing various substituents at para- or neighboring positions of the resveratrol A ring. They concluded that the partial substitution of 3,5-dihydroxy with methyl and benzene rings exerted an inhibitory effect on the viability of pancreatic cancer cells. Furthermore, the introduction of methyl substitutions enhanced lipophilicity and stability in human plasma, thereby facilitating improved gastrointestinal tract penetration, selectivity, and antiproliferative capacity [87].

Grau et al. synthesized a series of stilbene analogues and observed their antitumor effects in MIA PaCa-2 cells. Among these analogues, PT derivatives (Table 5) exhibited the most potent cytotoxicity with IC50 values of 28 ± 4 μM [22].

7. Antitumor SAR of PT derivatives

The stilbenoid PT is a naturally occurring compound, characterized by the dominant presence of trans-stilbene in its structure. Variations among natural stilbenoids primarily arise from differences in the type and number of substituents on the benzene ring, with hydroxyl and methoxy substitutions being more prevalent [88]. Hydroxyl groups replace hydrogen at the 3,5,4’ positions in natural stilbenoids compounds such as resveratrol. Isothapontigenin replaces the hydrogen atom at position 3’ of resveratrol with a methoxy group. Gnetol involves the substitution of hydroxyl groups at positions 3, 5, and 2‘,6.’ The naturally occurring stilbenoids were insufficient to meet the demand for their pharmacological activity in humans. To enhance the chemopreventive and/or therapeutic effects of cancer, chemists have introduced various groups such as isopentenyl, aminomethyl, phosphoric acid, glycoside, amide, etc., into the stilbenoid nucleus of stilbenes. The pharmacological activities and chemical properties of synthetic stilbenoids have been increasingly demonstrated. The modification of PT can be primarily categorized into two aspects: one focuses on the carbon-carbon double bond, while the other concentrates on the substituent group attached to the benzene ring (Figure 3).

Figure 3.

Constitutive relationship between PT and its derivatives.

7.1. Modification based on carbon-carbon double bonds

González-Sarrías et al. demonstrated that the presence of a styrene double bond in stilbene was the most crucial determinant for its antiproliferative activity, as evidenced by comparison with corresponding dibenzyl compounds [20]. In 2015, Madadi et al. synthesized diarylacrylonitrile analogues (1) and (2) by introducing cyano groups into the double bond of the stilbene scaffolds and incorporating methoxy substituents on the phenyl ring (Figure 4). Their findings revealed that both compounds (1) and (2) exhibit potential inhibition of acute myeloid leukemia cell line MV4–11 growth through interference with microtubule protein polymerization [89]. In 2020, Pecyna et al. discovered that the presence of a cis-configuration on the carbon-carbon double bond is indispensable for the biological activity of combretastatin A-4 (11), an analogue of PT. They further investigated modifications involving cyclization and acyclisation on the carbon-carbon double bond, respectively. It was observed that acyclic modifications, such as aliphatic amide derivatives, induced dose-dependent apoptosis and cell cycle arrest of A549 cells during the G2/M phase. Additionally, piperazine derivatives exhibited tubulin depolymerization and pro-apoptotic activities. On the other hand, cyclic modifications like aminoimidazole derivatives demonstrated potent cytotoxicity and microtubule depolymerization activity. Moreover, pyrazoline derivatives showed potential for inhibiting antioxidant enzymes leading to elevated ROS levels and thus resisting the growth of breast cancer MCF-7 cell line [90]. In 2023, Grau et al. substituted the central double bond with an unsaturated cyclic furan or pyrrole, leading to the synthesis of 2-arylbenzofuran-type derivatives or derivatives containing a 2-arylindole nucleus through oxygen atom incorporation. These compounds, particularly indole derivatives (3) and (4) featuring a -NH- group and para-methoxy moiety, were observed to exhibit moderate anti-angiogenic activity while enhancing cytotoxicity against pancreatic cancer [22].

Figure 4.

Modifications of PT and its derivatives based on carbon-carbon double bonds.

7.2. Modification based on benzene ring substitutions

7.2.1. Hydroxyl substitutions

Constitutive studies conducted by Murias and Wen et al. have demonstrated that augmenting the number of ortho positions of hydroxyl (OH) groups on the stilbenol ring enhances both cytotoxic activity [91] and antioxidant activity [92]. In 2004, Murias et al. synthesized a series of methyloxylated and hydroxylated PT derivatives and assessed their inhibitory potential against cyclooxygenase-1 (COX-1) and COX-2 enzymes. The results revealed that hydroxylated PT derivatives exhibited superior inhibition toward COX-2, while no significant inhibition was observed with methoxylated PT derivatives [93]. In the same year, Cheng et al. reported that 3’-hydroxypterostilbene (5) exhibited significant COX-2 inhibition and demonstrated stronger anti-colon cancer effects than PT in both in vivo and in vitro studies [19]. In their 2022 study, González-Sarrías et al. investigated the IC50 values of dietary stilbene, its gut microbial metabolites, and various analogues in human colon cancer cells. Their findings revealed that 4-hydroxystilbene (6) exhibited higher cytotoxicity compared to PT [20]. In 2023, Florio et al. incorporated various para- or neighboring substituents while preserving the 4’-phenol moiety to synthesize a series of derivatives with partial substitution of the 3,5-dihydroxy group by methyl and benzene rings. The derivative (7) exhibited diverse antitumor effects, alongside the identification of antioxidant potential associated with the 4’-OH group [87].

7.2.2. Methoxy substitutions

Although hydroxylated stilbene analogues exhibit significant therapeutic potential owing to their diverse biological and pharmacological activities, their rapid metabolism and limited bioavailability may impose constraints on their clinical application [94]. Giacomini et al. demonstrated that the introduction of modifications, such as methoxylation, to polyphenol structures can enhance their lipophilicity. This enhancement facilitates cellular uptake, prevents degradation, and improves stability [88]. In 2011, Hasiah et al. investigated the SAR of cytotoxicity and antioxidant activity in six methoxylated stilbene analogues. They discovered that the cytotoxicity and antioxidant activity of these compounds were dependent on their structural characteristics. Notably, (Z)-3,4,4’-trimethoxydiphenylethene (8) exhibited a more potent antiproliferative effect than PT in HepG2 cells [63]. In 2017, Bukhari et al. conducted a series of derivative synthesis and SAR studies on lipid-lowering drugs (11) with the aim of developing more potent inhibitors of microtubule protein polymerization. Their findings revealed that the biological activity of these drugs is highly dependent on the number and position of methoxy groups, particularly the 3,4,5-trimethoxy portion on ring A which was found to be associated with cytotoxicity and antitumor activity [95]. In 2019, Van den Brand et al. conducted a study on PT and several structurally similar stilbene compounds, revealing that trans-2,3,’4,5’-trimethoxystilbene (9) exhibited selective inhibition of the cell cycle in breast tumor cells and demonstrated enhanced suppression of breast cancer cell migration [41]. In the same year, Lu et al. conducted a screening of multiple gefitinib-resi stant NSCLC cell lines using the MTT assay and discovered that 3,5,4’-trimethoxystilbene (10), a PT derivative, enhanced the sensitivity of NSCLC cells to gefitinib while inducing apoptosis [79]. In 2022, Huber et al. conducted a biotransformation reaction on a mixture of resveratrol and PT, resulting in the generation of a diverse range of derivatives distributed across six distinct scaffolds. The subsequent analysis of SAR revealed that the presence of methoxy substituents potentially exerts a favorable impact on the inhibition of Wnt activity. The presence of highly similar structure-determining clusters, optimally positioned on distinct backbones, was hypothesized in these compounds based on the pharmacophore modeling hypothesis developed by the research team [46].

7.2.3. Halogen substitutions

In 2009, Moran et al. synthesized a series of trans-fluorinated analogues based on the diphenylethylene structure, which were subsequently evaluated in lung cancer and melanoma cell lines. One of the difluoro derivatives has demonstrated potent antiproliferative effects in breast, lung, and central nervous system tumors, as well as exhibiting significant antitumor activity across a range of human tumor cells, particularly leukemia cells. Additionally, the difluoroacetyl derivatives exhibited characteristics of multidrug resistance modifiers and demonstrated synergistic effects against tumor cell proliferation [96].

In 2016, Liu et al. synthesized a series of fluorinated stilbenes through substitution and Wittig-Horner reactions, followed by an analysis of their tectonic relationships by comparing the IC50 values with those of two controls, namely resveratrol and tamoxifen. They found that the B-ring 4’-site -OCF3-substituted derivatives had a stronger inhibitory effect on the proliferation of MCF-7 cells than the -SCF3-substituted derivatives; the A-ring 4-site-substituted derivatives had a stronger inhibitory effect on the proliferation of MCF-7 cells than the 3,4,5-site-substituted derivatives; and the B-ring inter-substituted derivatives of electron-withdrawing groups had a stronger inhibitory effect on the proliferation of MCF-7 cells than the para-substituted derivatives of electron-withdrawing groups. Moreover, 3,5-dimethoxy,3’-trifluoromethoxystilbene (12), which has a common A ring with PT, had the strongest inhibitory effect on the proliferation of MCF-7 cell [97].

7.3. Others

The PT-isothiocyanate (13) represents a novel class of hybrid compounds, wherein isothiocyanate functionality is introduced onto the backbone of PT. The compound (13) exhibited antitumor proliferative and metastatic effects in breast cancer cell lines MDA-MB-231 and MCF-7, as well as in mouse models of 4T1 cell-induced metastasis and loaded Ehrlich ascites tumors. These effects were potentially mediated through the regulation of the peroxisome proliferator-activated receptor γ activation pathway. Also The compound (13) exhibited superior anti-NF-κB and anti-inflammatory activities compared to PT in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage and keratan gum-induced rat paw edema models [98–101]. Moreover, (13) effectively modulated the AR in LNCaP cells expressing the T877A mutant AR, resulting in apoptosis induction in prostate cancer cells. The suppression of cell proliferation and promotion of apoptosis by compound (13) were partially mediated through the inhibition of AR, Akt, and ERK signaling pathways. The IC50 values for compound (13) were determined to be 50 ± 50.40 μM and 1 ± 12.45 μM in AR-positive (LNCaP) and negative (PC-1) cells, respectively [99].

In 2010, Belluti et al. synthesized a series of derivatives (14) and (15) that incorporate coumarin into the stilbene framework. The aforementioned class of compounds was discovered to augment the antiproliferative activity of H460 human lung cancer cells and exhibit significant pro-apoptotic effects [88,102]. In 2012, Moser et al. found that benzimidazole analogues of stilbene exhibited soluble epoxide hydrolase (sEH) inhibition [103]. In the subsequent year, Buscató et al. designed and synthesized a series of compounds based on the (E)-benzimidazole stilbene scaffold. Among these compounds, the 2-trifluoromethyl substituent (16) exhibited the lowest IC50 value (~0.6 μM) and effectively inhibited U937 cell proliferation [104].

8. Bioavailability

Some commonly occurring stilbenes, such as resveratrol, exhibit relatively low bioavailability due to their incomplete absorption and rapid metabolism within the gastrointestinal tract [105]. Owing to the presence of two methoxy groups and one hydroxyl group, PT demonstrates enhanced lipophilicity and increased potential for cellular uptake in comparison with resveratrol, which contains three hydroxyl groups [106]. Additionally, extensive research has demonstrated that PT exhibits superior bioavailability and bioactivity, along with a prolonged half-life compared to resveratrol under identical experimental conditions [4,107–109]. In terms of pharmacokinetics, PT is readily absorbed in the gastrointestinal tract and demonstrates extensive distribution to various tissues and organs throughout the body via systemic circulation. The ADME study conducted by Prasad et al. revealed that PT exhibits high lipophilicity, low water solubility, and BBB permeability, suggesting its potential impact on the systemic and central nervous system. Furthermore, PT is primarily metabolized by the hepatic cytochrome P450 enzyme system, including various subtypes such as CYP1A2, CYP2C9, and CYP3A4. The resultant metabolites predominantly comprise glucose-aldoxylation products and sulfated derivatives [110–112]. Currently, the available routes of administration include oral, intravenous, or local administration; however, the sole administration of PT often hampers its bioavailability and partially compromises its anti-cancer efficacy [94,113–115]. In order to enhance the clinical bioavailability of PT, common strategies include the modification of PT prodrugs [116,117], nanoparticle synthesis [118], and other carriers for transportation, as well as the formation of eutectic mixtures. The incorporation of PT nanoparticles significantly improves water solubility and drug release, demonstrating exceptional stability under physiological conditions. Notably, certain PT nanoparticles demonstrated superior antitumor activity compared to pure PT [5,6,32,62]. The drug solubility can be significantly enhanced through the formation of co-crystals, as demonstrated by the examples of piperazine-pterostilbene co-crystals [119] and caffeine co-crystals [120]. Clinical trials are currently underway for the oral bioavailability of PT co-crystals in comparison to their free form (BIOPTERO) (Bioavailability- NCT05561075).

Stilbene structure is one of the most important anticancer pharmacophores. A number of stilbene-based drugs, such as raloxifene, toremifene, or tamoxifen, have already been approved for clinical use [121]. A number of compounds with a stilbene structure are also under clinical trial for oncological applications, such as resveratrol (colorectal cancer-NCT00920803, multiple myeloma-NCT00920556, chronic obstructive pulmonary disease – NCT03819517); the combretastatin A4 phosphate (advanced Anaplastic Thyroid Cancer-NCT00060242, advanced Solid Tumors-NCT00003768, NCT00003698); and the vascular disrupting agent OXI-4503 (acute myeloid leukemia and myelodysplastic syndromes – NCT02576301). Exploration of the clinical application of pterostilbene began as early as 2016 (amyotrophic lateral sclerosis – NCT05095571), with additional clinical trials initiated in 2019 and 2020 for acute kidney injury (NCT04342975) and endometrial cancer (NCT03671811), respectively. Moreover, certain derivatives have demonstrated enhanced bioavailability compared to PT, thereby warranting further investigation. Peng et al. discovered that trans-3,5,3‘,4’-tetramethoxystilbene (50.5%) exhibited significantly higher oral bioavailability than PT (12.5%) and other tetramethoxystilbenes [109]. In addition to the formation of eutectic crystals, González-Alfonso et al. discovered that α-glucosylation of PT also enhanced its water solubility to approximately 0.1 g/L. Furthermore, they demonstrated that PT α-d-glucopyranoside exhibited lower toxicity than PT toward human SH-S5Y5 neurons, MRC5 fibroblasts, and HT-29 colon carcinoma cells [122]. In addition, CA-4 (11), a small molecule vascular-targeting agent that exhibits antivascular activity below the maximum tolerated dose, demonstrated remarkable growth inhibition against the NCI 60 human tumor cell line (with IC50 values ranging from 0.53 to 2.4 μM) and selectively suppressed neovascularization in cancerous tissues. Currently, it is undergoing clinical trials as an anti-tumor vascular disruptor (ovarian cancer- NCT02055690, neuroendocrine tumors- NCT02279602, etc.). However, (11) exhibits poor water solubility and stability, and the active cis-styrene configuration undergoes isomerization to the corresponding less active trans compound when exposed to heat, light, or hydrophilic media. In order to enhance its therapeutic potential, phosphorylated prodrugs of (11) have been extensively investigated for their anticancer effects in asexual thyroid, non-small cell lung, and ovarian cancers, both as standalone treatments and in combination with other drugs [88]. These findings offer valuable insights into strategies aimed at improving the bioavailability of PT and its derivatives.

By implementing diverse strategies to enhance the bioavailability of stilbenes, we can significantly amplify the clinical significance of these compounds and establish a robust foundation for future clinical trials.

9. Conclusion

In our investigation of various cancer treatment methods, we observed that PT and its derivatives exhibited potent anti-tumor activity. These compounds often demonstrated similar mechanisms of action, with some derivatives even surpassing the efficacy of PT itself. To facilitate the development and synthesis of novel pharmaceuticals, we further investigated the underlying structural factors responsible for the potent anti-tumor activity exhibited by these derivatives. Simultaneously, we have comprehensively summarized the strategies for enhancing the bioavailability of PT and extensively explored the potential application of its derivatives in terms of bioavailability, thereby establishing a solid foundation for chemical modification and clinical utilization of stilbenes.

10. Future prospective

In terms of anti-tumor activity, some excellent PT derivatives necessitate further in vivo and clinical testing to ascertain their efficacy. Reinforcement of the validation process for these compounds will contribute to bridging the existing gaps in clinical efficacy or safety, thereby expediting the advancement of novel drug development. In terms of bioavailability, in addition to enhancing the utilization rate of PT itself, we can also direct our attention toward derivatives exhibiting promising clinical potential, thereby achieving the dual optimization of clinical efficacy and cost-effectiveness. Furthermore, PT not only exerts its effects as a monotherapy in various types of cancer, but also demonstrates potential as an adjunctive or combination therapy to enhance treatment efficacy. The investigation of the synergistic effect of PT holds significant clinical implications. In the context of clinically aggressive estrogen receptor-alpha (Erα)-negative breast cancers, epigenetic-based interventions such as histone deacetylase (HDAC) inhibitors can be employed to modulate ERα expression; however, they often entail a multitude of adverse effects. Rishabh et al. demonstrated that the combination of PT and resveratrol effectively down-regulated SIRT19, a type III histone deacetylase, thereby influencing DNA damage and response mechanisms. This combined therapy induced cell cycle arrest at G2/M and S-phase as well as apoptosis. Additionally, it exhibited enhanced efficacy in augmenting ER-α expression while mitigating the adverse effects associated with hormone-refractory breast cancer [20]. Similar cumulative effects can be observed when combining PT with curcumin analogues, leading to the activation of lysyl oxidase and subsequent inhibition of migration and invasion in hepatocellular carcinoma cells [61]; The combination of PT and EGCG effectively suppressed the proliferation and induced apoptosis of pancreatic cancer cell lines MIA PaCa-2 and PANC-1 by modulating distinct points in the mechanistic pathway [85]. Moreover, PT holds the potential to augment the efficacy of chemoradiotherapy while mitigating adverse effects, rendering it a viable adjunct to conventional therapy. EGFR mutation-positive NSCLC cells typically develop resistance to Osimertinib monotherapy by activating compensatory pathways in parallel. The combined treatment of PT and Osimertinib exhibited a synergistic effect, overcoming this resistance in PC9 cells while also reversing the osimertinib-induced phosphorylation of STAT1, YAP1, and CUB structural domain protein-1 (CDCP1), as well as inhibiting Src phosphorylation [123]. Mannal et al. reported that the combination of Tamoxifen, a clinically used drug for advanced breast and ovarian cancers, with PT exhibits a cumulative inhibitory effect on breast cancer cells, possibly attributed to its augmentation of apoptosis [31]. These synergistic effects can enhance the drug sensitivity of tumor cells and mitigate tolerance or toxicity, thereby creating favorable conditions for the synthesis of novel therapeutic agents with potential efficacy in cancer therapy, in conjunction with the aforementioned studies and advancements in administration methods.

Funding Statement

The authors acknowledge Shandong Province Chinese medicine science and technology project youth project [Q-2023097]; NATCM’s Project of High-level Construction of Key TCM Disciplines Marine Traditional Chinese Medicine; [No. zyyzdxk-2023124]; Shandong University of Traditional Chinese Medicine [2023058, 2023060] for financial support.

Article highlights

• Stilbene structure is one of the most important anticancer pharmacophores.

• The comparative analysis of the anti-cancer pharmacological activity and mechanism of pterostilbene and its derivatives in various types of cancer is presented.

  • PT and its derivatives against colon cancer

  • PT and its derivatives against breast cancer

  • PT and its derivatives against liver cancer

  • PT and its derivatives against lung cancer

  • PT and its derivatives against pancreatic cancer

• The structure-activity relationship analysis of pterostilbene and its derivatives with diverse modified architectures is discussed.

  • Modification based on carbon-carbon double bonds

  • Modification based on benzene ring substitutions

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.