Magnolol and its semi-synthetic derivatives: a comprehensive review of anti-cancer mechanisms, pharmacokinetics, and future therapeutic potential

Abstract

In recent years, magnolol (MG), a natural active compound of polyphenolic nature, has garnered significant interest for its anti-cancer effects. Numerous studies conducted on cell lines and animal models have indicated a positive impact of administering drugs or semi-synthesized products derived from MG, including a decreased incidence of various cancers. This review aims to illustrate the underlying cellular and molecular basis of its actions. The article includes in-depth explanations of phytochemistry, semi-synthetic derivatives, bioavailability, pharmacokinetics, preclinical research, anti-tumor mechanisms, human clinical studies, toxicity, side effects, and safety. It also demonstrates that, in contrast to the wealth of synthetic medications, MG is highly effective against bladder, colon, gastric, skin, liver, lung, gallbladder, and prostate cancers. The findings of this review indicate that MG is a promising candidate as an anti-tumor agent, and future research should focus on developing new semi-synthetic derivative compounds with potential anti-tumor properties.

Introduction

Forecasts for cancer incidence and mortality indicate that by 2030, the annual number of cancer diagnoses will exceed 2 million [1], with projections ranging from 2.2 million to nearly 3 million cases by 2050 [2]. The rise in diagnosis rates is expected to outpace population growth during this period [1]. In 2022, people born in the USA have approximately a 40% (men) and a 38% (women) risk, respectively, of being diagnosed with cancer in their lifetime [3]. Therefore, the expected increase in cancer diagnoses underscores the urgent need for enhanced prevention, early detection, and treatment strategies to tackle this growing public health challenge.

Cancer is the uncontrolled growth of abnormal cells that can invade nearby and distant tissues and organs. It involves changes in cellular or tissue structure and function. Genetic mutations are the predominant cause of the growth of neoplastic cells, which tend to increase their reproductive lifespan. The most common cancers in men are prostate, lung/bronchus, colon/rectum, and urinary bladder; in women, they are breast, lung/bronchus, colon/rectum, uterine corpus, and thyroid [4].

On the other hand, the two most common cancers in children are blood cancer and cancers of the brain and lymph nodes [5]. Cancer can affect anyone at any age but is more likely to occur in older people, and the treatment depends on the disease stage and type of cancer.

In this sense, Magnolol (MG) is a hydroxylated biphenyl compound derived from the bark (roots and branches) of Magnolia species such as M. officinalis, M. obovata, and M. grandiflora [6]. Historically, the genus Magnolia represents plants of the family Magnoliaceae, which commonly grow in the valleys and mountains of China, Japan, and Korea [7, 8]. The two main bioactive compounds isolated from these plants are MG (5,5ʹ-diallyl-2,2ʹ-dihydroxybiphenyl) and Honokiol (3,5ʹ-diallyl-4,2ʹ-dihydroxybiphenyl) (Fig. 1) which are phenolic regioisomers [9]. MG is a nonpolar compound with a white fine powder appearance and with a melting point of 102 °C. In the bark extracts of Magnolia plants, the composition of MG ranges from 1 to 10%, while Honokiol comprises 1 to 5%. In both cases, variation in composition generally depends on environmental and developmental conditions such as genetic origin, altitude, temperature, and plant age [10]. In the last few decades, MG has demonstrated a broad spectrum of biological activities against cancer, affecting various aspects of cancer cell biology, such as proliferation, cell cycle, apoptosis, metastasis, angiogenesis, and signaling pathways, such as NF-κB (Nuclear factor-KappaB), MAPK (Mitogen-activated protein kinase), and PI3 K/Akt/mTOR (Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) [11]. MG inhibits cancer cell growth in bladder [12], breast [13], cholangiocarcinoma [14], colon [15], esophagus [16], fibrosarcoma [17], gallbladder [18], gastric [19], glioblastoma [20], leukemia [17], liver [21], lung [22], lymphoma [23], melanoma [24], oral carcinoma [25], osteosarcoma [26], ovarian [26], pancreatic [27], prostate [28], renal [29], skin [30], and thyroid [31] cancer. MG acts through multiple anti-tumor mechanisms such as inhibition of DNA synthesis, induction of apoptosis in human liver and colon cancerous cells [32], suppression of gallbladder cancer cell growth via p53 [18], and promotion of autophagy to cause cell death in lung cancer cells [33]. Thus, MG has emerged as a promising anti-cancer drug; nevertheless, its low bioavailability and solubility limit its potential clinical application. Therefore, developing a delivery system that can solve these limitations [34] is essential. MG also possesses a variety of pharmacological effects, including anti-oxidant [35], anti-inflammatory, anti-bacterial [36], anti-thrombotic or anti-platelet [37], anti-stress [38], anti-anxiety, anti-Alzheimer [39], Alzheimer, anti-stroke[40], hypoglycemic [41], smooth muscle relaxant [42], weight control [43], anti-dyspeptic/prokinetic [44], anti-epileptic[45] and hepatoprotective effects [46]. Therefore, this review provides a comprehensive overview of the impact of MG and its semi- synthetic derivatives on the molecular targets and signaling pathways involved in cancer cell growth and metastasis, as well as their toxicity, bioavailability, pharmacokinetics, and formulations of MG.

Fig. 1.

Structures of magnolol, honokiol and magnolol-2-O-glucuronide

Review methodology

We conducted a comprehensive review of the anti-cancer properties of MG based on published research investigating its effects against various types of cancer. We searched Google Scholar, PubMed, and the American Chemical Society for articles related to “Magnolol and (cancer or tumor or carcinoma)” from 1986 to 2024. We focused on studies that examined the anti-cancer effects of MG and its semi-synthetic derivatives, as well as those exploring the anti-cancer mechanisms of MG, its bioavailability, and pharmacokinetics. Additionally, we analyzed MG’s pharmacological investigations and clinical studies, including only English-language publications.

Molecular docking

We performed molecular docking using Molegro Virtual Docker (MVD) 6.0 to determine if MG interacts with PI3 Kα (PDB:4 TV3), PI3 Kγ (PDB:7 JWE), and GSK-3beta (PDB:5 K5 N), which are critical regulators of cellular functions in cancer cells. Additionally, we accessed the Gedatolisib PubChem database (#44516953), which demonstrates potential activity in cancer cells targeting PI3 K and the PI3 K/mTOR signaling pathway. This database revealed a high affinity for the active sites of PI3 Kα, PI3 Kγ, and GSK-3beta. The docking parameters included a Moldock Score with a GRID resolution of 0.30, the MolDock SE algorithm, a maximum of 1500 iterations, a maximum size of 50, a generation energy position threshold of 100, and five multiple poses; the working radius was set to 15. The docking was conducted in the active site. The molecule was prepared by removing water molecules and cofactors from the PDB molecule. The structure used for docking was MG, which was obtained from the PubChem database (#72300). The working coordinates were as follows: for (PI3 K) α (x: − 15.87, y:, and z: 27.28), PI3 Kγ (x: 26.15, y: 2.94, and z: 20.12), and GSK-3beta (x: 1.13, y: 9.35, and z:26.27).

Sources and phytochemistry of magnolol

MG is a polyphenol belonging to the lignans structural group and was originally isolated from a plant used in Chinese and Japanese medicine to treat various conditions, including anxiety, fever, headache, and neurosis [44]. It also reduces the body’s temperature by inhibiting the release of 5-hydroxytryptamine in the rat hypothalamus [45]. The IUPAC name of MG is 2-(2-hydroxy-5-prop-2-enylphenyl)−4-prop-2-enylphenol, and it is also known by other names such as 5,5ʹ-diallyl-2,2ʹ-dihydroxybiphenyl, 2,2ʹ-bichavicol, and 5,5ʹ-diallyl-(1,1ʹ-biphenyl)−2,2ʹ-diol [3]. MG and honokiol are the main constituents of the leaf and bark of different Magnolia species, such as M. officinalis, M. dealbata, and M. obovate [37]. These are stereoisomers, and their structures are presented in Fig. 1. MG exhibited greater solubility in basic and lower solubility at acidic pH values [46]. Its unique pharmacophore structure, which consists of two hydroxylated aromatic rings connected by a single C–C bond representing the hydroxylated biphenyl structure, plays a significant role in its biological activity [47]. The structural characteristic enables interactions with numerous proteins [47]. MG alters its structure inside the different organs, forming magnolol-2-O-glucuronide and MG sulfate, both of which possess enhanced pharmacological properties [48]. Notably, many phytochemicals isolated from natural sources, such as flavonoids, alkaloids, polyphenols, diterpenoids, and sesquiterpenes, exhibit anti-cancer properties [49]. Additionally, MG has beneficial activities that include anti-cancer, antibiotic, antispasmodic, and antidepression effects [48], anti-inflammatory antioxidants, and tumor-suppressive properties [50]. Furthermore, MG can protect DNA from oxidation caused by 2,2′-Azobis (2-amidinopropane) dihydrochloride and can effectively trap 1.8 and 2.5 radicals [51].

Semi-synthetic derivatives

Structural modifications of MG have led to the development of semi-synthetic derivatives with various structural variants that provide new and improved pharmacological properties; some have shown approximately 10- to 100-fold greater cytotoxicity than MG. For instance, an MG derivative, 3-(4-aminopiperidin-1-yl) methyl magnolol, exhibited an eightfold increase in potency against HCC827, H1975, and H460 cell lines. This finding suggests that it may be a promising candidate for treating non-small cell lung cancer (NSCLC) [47]. The derivative (Fig. 2, structure A) was synthesized by adding halohydrocarbons and removing t-butyloxycarbonyl under acidic conditions. A Friedel–Crafts alkylation reaction is conducted on MG, involving the addition of a halohydrocarbon to MG. Friedel–Crafts alkylation is an electrophilic substitution reaction where an alkyl group attaches to the benzene ring of MG. At this point, an intermediate product can form with t-butyloxycarbonyl. The subsequent step entails removing the t-butyloxycarbonyl group under acidic conditions, which releases the t-butyloxycarbonyl group and regenerates the functional group on the benzene ring. The resulting compound is treated with potassium carbonate (K₂CO₃) and acetonitrile (MeCN). This step may relate to neutralizing residual acids and purifying the product. Nitrogen (N₂) indicates that the reaction occurs under an inert atmosphere. The reaction proceeds at 95 °C for 3 to 12 h. The objective was to introduce another functional group to the product or conduct a substitution reaction [47].

Fig. 2.

Semi-synthetic magnolol derivative. A Friedel–Crafts alkylation introduces a halohydrocarbon to MG, adding an alkyl group to the benzene ring. The intermediate product undergoes deprotection in acidic conditions, and the compound is purified using potassium carbonate (K₂CO₃) and acetonitrile (MeCN). The reaction is conducted under nitrogen (N₂) at 95 °C for 3–12 h to introduce a functional group or perform a substitution

On the other hand, an MG derivative was produced using a Suzuki coupling reaction catalyzed by Pd (Fig. 3, Compound B). Alkylation with n-butyl lithium (nBuLi) and tribromomethoxymethane (Br(OMe)₃) in tetrahydrofuran (THF): In this step, a trisubstituted benzene (with a methoxy group (OMe) in position 1 and bromine (Br) in position 2) reacts with nBuLi and Br(OMe)₃ in THF at − 78 °C for 2 h. The reaction involves Friedel- Crafts alkylation. nBuLi is a strong base that deprotonates the benzene meta to the OMe group, after which Br(OMe)₃ acts as an electrophile in the Friedel-Crafts reaction. Suzuki coupling with Pd(PPh₃)₄ and Na₂ CO₃ in DME: in this stage, the product (which now has Br(OMe)₃ instead of bromine) reacts with palladium (Pd) as a catalyst (Pd(PPh₃)₄) and sodium carbonate (Na₂ CO₃) in diethyl ether dimethyl (DME) at reflux for 6 h. This step involves a Suzuki coupling reaction, a cross-reaction between an organic compound containing a benzene group and a compound containing a boron group (usually an aromatic molecule with a boron group). Pd(PPh₃)₄ catalyzes the formation of a carbon–carbon bond between the two molecules. Substitution of OMe for OH and addition of I in the meta position: In this stage, the product from the previous stage (which has two disubstituted benzenes attached) reacts with iodide (I₂) in the presence of CAN and acetonitrile (CH₃ CN) at room temperature for 2 h. Following that, a reaction with aluminum chloride (AlCl₃) and dimethyl sulfide (Me₂S) is performed at room temperature for 1 h. These steps involve a nucleophilic aromatic substitution in which methoxy (OMe) groups are replaced by hydroxyl (OH) groups on each disubstituted benzene, and an iodine atom is added at a meta position to the former location of the OMe group. The presence of CAN and AlCl₃ serves as deprotecting agents to facilitate the substitution and addition of the iodine group. A panel of three human cancer cell lines, including PC-3 (prostate cancer cells), HL-60 (human promyelocytic leukemia cells), and MOLT-4 (human acute lymphoblastic leukemia cell line), was used to assess the compound’s in vitro antiproliferative potential. Compound B with diiodo and butyl substitutions was tested against these cell lines, revealing cytotoxicity with IC ₅₀ values of 2, 2, and 10 µM, respectively [52].

Fig. 3.

Production of MG derivative via Pd-catalyzed Suzuki coupling. Alkylation with nBuLi and Br(OMe)₃ in THF yields a trisubstituted benzene. The product undergoes Suzuki coupling with Pd(PPh₃)₄ and Na₂CO₃ in DME at reflux for 6 h. The final substitution replaces OMe with OH and introduces iodine (I) at the meta position, using I₂, CAN, acetonitrile, AlCl₃, and Me₂S at room temperature

Other derivatives were obtained when the naturally isolated MG was subjected to the Williamson ether synthesis reaction, yielding new products (Fig. 4, structures C and D). In this stage of the Williamson ether reaction, the compound from the previous step (which has two disubstituted benzenes linked by OH groups) is reacted with sodium carbonate (Na₂CO₃) and dimethylformamide (DMF). Na₂CO₃ acts as a base to deprotonate the OH group, forming O-Na+ (a sodium alkyloxide ion). This ion then reacts with an alkyl halide (a compound with an alkyl group attached to a halogen atom, such as Cl, Br, or I) to replace the sodium ion with an alkyloxy group (OR), leaving OR in place of O-Na+. This step in the synthesis is known as a Williamson ether reaction. Here, a sodium alkyloxide ion is formed from the OH group in disubstituted benzene and reacts with an alkyl halide to form an alkyloxy ether. This reaction produces two products: one with an OR group on the first benzene and another with an OR group on the second benzene, replacing the initial OH groups. The new products are MG derivatives with alkyloxy groups instead of hydroxyl groups, potentially modifying their chemical properties and applications. The compounds produced more effective in vitro antiproliferative effects against MD-NB-231, SMMC-7721, MCF-7, and CNE-2Z human cancer cell lines than MG. Derivative C was especially effective against MDA-MB-231 cells, with an IC₅₀ value of 20.43 µM, and it also reduced the migration and invasion of this cell line by lowering the protein levels of HIF-1α (Hypoxia-inducible factor 1 alpha), MMP-9 (Matrix metalloproteinase-9), and MMP-2 (Matrix metalloproteinase-2). The cytotoxicity of the compound increased by having a para-F-substituted benzyl group instead of ortho or meta position [48]. Thus, replacing the phenolic hydroxyl group of MG with a para-fluorobenzyl group enhances cytotoxic potency.

Fig. 4.

MG derivatives were obtained through Williamson ether synthesis. The product from the previous reaction interacts with Na₂CO₃ and DMF, resulting in a sodium alkyloxide ion. This ion subsequently reacts with an alkyl halide, replacing the OH group with an OR group and leading to two products featuring alkyloxy groups instead of hydroxyl groups

Other semi-synthetic derivatives of MG were synthesized through an esterification reaction (Fig. 5). The hydroxyl group (OH) of MG reacts with n-propyl acid chloride (nPrCOCl) to form an ester bond. Potassium carbonate (K₂CO₃) acts as a base to neutralize the hydrochloric acid (HCl) produced during the reaction. Acetone and room temperature (r.t.) are suitable solvents and reaction conditions. The products of this reaction are the monoester and diester of MG, indicating that one or both OH groups of MG have been converted into ester groups, depending on the specific conditions of the reaction. These esters are semisynthetic derivatives of MG and may have applications in chemistry and pharmacology, as modifying functional groups in a molecule can alter its properties and biological activities. The butyrate ester, combined with parental MG (OH group), demonstrated potent antiproliferative activity and promising pharmacological action against hepatocellular carcinoma. MG’s mono and dibutyrate derivatives showed significant cytotoxic effects against HepG2 cells after 48 h. The study indicated that the dibutyrate product elicited higher activity than MG at concentrations as low as 1 µM [49].

Fig. 5.

Semi-synthetic magnolol derivatives synthesized through esterification with n-propyl acid chloride (nPrCOCl) and K₂CO₃. This reaction produces both monoester and diester derivatives

A derivative produced by a Mannich reaction (Fig. 6) exhibited cytotoxicity in cancer cells by inducing autophagy. The compound was obtained by substituting hydrogen at the C-2 position of MG with a Mannich base. Initially, 4,5-trimethoxybenzaldehyde reacts with morpholine to form a Mannich base. This Mannich base, which contains an amino group (NH₂), is then reacted with MG. The Mannich reaction is an organic process involving the condensation of a ketone or aldehyde, a compound with a primary amino group (such as morpholine in this case), and a compound with an active group like a methylene ion (-CH₂-). This reaction is employed to form Mannich bases, which are reactive intermediates that can be used to synthesize various chemicals. MG reacts with the produced Mannich base, resulting in the formation of the semisynthetic MG derivative. The Mannich reaction can introduce specific functional groups into MG, potentially modifying its chemical properties and applications. The exact nature of the MG derivative will depend on the structure of the Mannich base and the reaction conditions applied. The derived compound (G) was tested alongside cisplatin against human cancer cell lines, demonstrating promising antiproliferative effects against HeLa, T47D, and MCF-7 cancer cell lines, with IC50 values of 1.71, 0.91, and 3.32 µM, respectively. The MG derivative (G) exhibited significantly higher cytotoxicity on the T47D cancer cell line, being 10.3 times more effective than MG [50].

Fig. 6.

Synthesis of a magnolol derivative via the Mannich reaction. The Mannich reaction involves the condensation of a ketone or aldehyde, a primary amino group (such as morpholine), and an active methylene group (–CH₂–). This reaction produces a Mannich base that can subsequently react with MG, resulting in a semisynthetic MG derivative that may modify its chemical properties and applications

Studies comparing the anti-cancer activities of MG derivatives are limited. Zhao et al. demonstrated that the MG derivative C2, 3-(4-aminopiperidin-1-yl)methyl magnolol exhibits superior activity compared to honokiol. Additionally, the authors synthesized fifty-one MG derivatives, with compound 30 showing the strongest antiproliferative effects on H460, HCC827, and H1975 cell lines, with IC₅₀ values ranging from 0.63 to 0.93 μM. The activity is approximately 10 to 100 times greater than C2 and MG, respectively [47]. In comparison, IC₅₀ values for compound B tested against HL-60, PC-3, and MOLT-4 cell lines were 2, 2, and 10 µM [52], while derivative C produced an IC₅₀ of 20.43 µM against MDA-MB-231 cells [48], and compound G had IC₅₀ values of 1.71, 0.91, and 3.32 µM for HeLa, T47D, and MCF-7 cells, respectively [50]. However, further research is necessary to identify the most effective derivative.

Mechanism of anti-tumor action of magnolol

MG exerts its anti-cancer effects through multiple mechanisms involving various signaling pathways (Figs. 7 and 8). This section discusses the mechanisms of action of MG as elucidated by other cancer models. We summarize evidence that MG can induce cell cycle arrest and apoptosis, suppress cell growth and proliferation, and prevent angiogenesis. Additionally, we explore the molecular pathways involved in MG’s anti-cancer actions, including PI3 K/Akt/mTOR, MAPK, and NF-κB (Fig. 8). Based on existing evidence, we can conclude that MG possesses multi-target anti-cancer activity, a trait attributed to MG’s distinctive symmetrical bi-phenol structure, which makes it ideal for interacting with protein molecules [53].

Fig. 7.

The active site is similar to Gedalotisib (green) and Magnolol (red)

Fig. 8.

Magnolol induces cell cycle arrest and apoptosis and suppresses cell growth and proliferation; it prevents angiogenesis. Magnolol acts in molecular pathways involved with anti-cancer actions, such as PI3 K/Akt/mTOR, MAPK, and NF-κB

Suppression of growth and proliferation

Cell proliferation is the process by which many diploid cells are produced from a single cell through growth and the cell cycle, and it is regulated by both external and internal factors [54]. Proliferation is a critical characteristic of cancer, which is marked by abnormal growth. While normal cell growth is tightly regulated, tumor cells lose this regulation during tumor formation and metastasis, resulting in a lack of standard growth control [55]. Understanding this transition aids in identifying how cancer begins and in improving treatment methods that do not harm normal cells [55]. MG can inhibit the growth of cells in various cancer types, including those from the bladder [12], breast [56], cholangiocarcinoma [14], esophageal [16], gastric [19], leukemia [17], liver [57], lung [22], lymphoma [23], melanoma [24], oral carcinoma [25], pancreatic [27], and skin [30] cancers.

Inhibition of signaling (PI3 K/Akt/mTOR/MAPK/NF-kB)

The PI3 K/Akt/mTOR signaling pathway is often involved in the growth and survival of cancer cells [58]. This pathway is activated when PI3 K converts phosphatidylinositol (3,4-bisphosphate) to phosphatidylinositol (3,4,5)-triphosphate (PIP3), which leads to the phosphorylation of Akt and the mTOR complex 1 (mTORC1) [59, 60]. mTOR regulates the production of many proteins that promote proliferation by phosphorylating p70S6 kinase (p70S6 K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) [61]. MG has decreased the phosphorylation of PI3 K, Akt, mTOR, p70S6 K, and 4E-BP1 in various cancer types [11]. Therefore, MG can inhibit the PI3 K/Akt/mTOR signaling pathway and reduce tumor cell growth; this MG-induced inactivation appears independent of cancer type. MG also impacts the MAPK signaling pathway, another critical signal transduction pathway [62]. MG targets the three main MAPK cascades: MAPK/ERK (Extracellular signal-regulated kinase), MAPK/C-Jun N-Terminal Kinase, and MAPK/p38 mitogen-activated protein kinase (p38). Finally, MG can also block the NF-κB signaling pathway by preventing the phosphorylation of IκB and/or the p65 NF-κB subunit, essential for regulating tumor growth and metastasis [57].

Regarding molecular docking, our results indicate that Gelatoditosib interacts with the active site of PI3 Kα, binding to amino acids such as Val 851, Ser 774, and His 917, and with PI3 Kγ, interacting with Val 882, Asp 841, and Gly 966, as illustrated in Fig. 7. Additionally, GSK3β is a crucial target due to its role in cancer, where it regulates multiple proto-oncoproteins and acts as an intermediary in the epithelial-mesenchymal transition. Its deregulation contributes to tumor cell survival, evasion of apoptosis, proliferation, invasion, maintenance of cancer stemness, and therapeutic resistance. Within the active site of GSK3β, essential amino acids such as Val 135 and Asp 133 play a key role in inactivating the site [63]. Other amino acids involved in this site include Arg 141, Glu 137, Thr 138, Val 70, Ala 83, Asp 133, Leu 188, and Tyr 134. When testing Gelatoditosib in the GSK3β active site, we found that it interacts specifically with these amino acids, achieving a Moldock score of −142.925, which confirms its reported high specificity for receptors involved in cancer.

Similarly, MG may interact with some of the same amino acids as Gelatoditosib, including Ile 932, Ser 774, and Asp 933 in PI3 Kα, and Asp 841, Asp 964, and Gly 966 in PI3 Kγ (Fig. 7, Table 1). These interactions may contribute to its anti-cancer properties. Although its binding energy is weaker than that of Gelatoditosib, MG can still interact at the PI3 K action site. In the case of GSK3β, MG forms hydrogen bonds with Val 135, Glu 137, Tyr 134, and Leu 188, suggesting that it interacts with critical amino acids to inhibit GSK3β. Therefore, MG could exhibit anti-cancer activity by interacting with and forming bonds at the action sites of PI3 K and GSK3β, as reported in the literature.

Table 1.

Comparative molecular docking analysis of Gedatolisib and Magnolol with PI3 Kα, PI3 Kγ, and GSK-3beta proteins

Molecules	PI3 Kα			PI3 Kγ			GSK-3beta
	Moldock Score	Hidrogen interactions	Steric interactions	Moldock Score	Hidrogen interactions	Steric interactions	Moldock Score	Hidrogen interactions	Steric interactions
Gedatolisib	− 105.839	Gln 859 Val 851 Ser 774	Ile 800, Asp 933 Ile 932, His 917 Ser 919	− 158.164	Asp 841 Val 882 Thr 887	Asp 837 Asp 964 Glu 880 Gly 966	− 142.925	–	Asn 64, Gly 63, Phe 67, Val 135, Leu 188, Asp 133, Ala 83 Leu 132, Asp 200, Gln 185 Cys 199, Lys 85 Val 70
Magnolol	− 91.334	Lys 802 Asp 933	Ile 932, Trp 780 Met 772, Ser 774, Tyr 836 Asp 810, Tyr 836, Asp 806 Ile 848	− 87.849	Tyr 867 Asp 964 Asp 841	Asp 836 Gly 966 Leu 838 Ile 831	− 91.6004	Val 135 Glu 137	Tyr 134 Leu 188

Arrest of cell cycle

One mechanism by which MG exerts its anti-cancer effects is by arresting the cell cycle at different phases, depending on the type of cancer cells. The cell cycle is a process that repeats from quiescence (G0 phase) to proliferation (G1, S, G2, and M phases) and then back to the G0 phase [64]. Cell cycle progression is mainly controlled by the phosphorylation of particular proteins by cyclin-dependent kinases (CDKs), their dephosphorylation by phosphatases, and specialized proteolytic degradation by the ubiquitin–proteasome system [11, 64]. Any disruption or alteration of the cell cycle can result in abnormal cell growth and proliferation, a hallmark of cancer. MG can stop the cell cycle in three phases: sub-G1 [65], G0/G1 [66], and G2/M MG [22]. While MG can reduce the number of cells in the G1 phase, it does not demonstrate the potency to prevent cancer from spreading.

Induction of apoptosis and inhibition of angiogenesis

The natural mechanism for programmed cell death in a cell is apoptosis, which is crucial for maintaining homeostasis and eliminating undesirable cells. This highly regulated process is triggered by DNA damage or uncontrolled growth [67]. MG can simultaneously activate both the intrinsic and extrinsic pathways of apoptosis, which are characterized by the loss of mitochondrial membrane potential and cleaved caspase-9 [20]. Circulating endothelial precursors, shed from the vessel wall or mobilized from the bone marrow, can also contribute to tumor angiogenesis [68]. Additionally, MG can inhibit blood supply to the cells by blocking angiogenesis.

Anti-oxidant effects

MG modulates oxidative stress due to its high radical-scavenging activities [11, 69]. A study demonstrated that MG reduces ONOO⁻ and O₂, trapping up to 2.5 radicals and protecting DNA from oxidation induced by the compound 2,2′-Azobis (2-amidinopropane) dihydrochloride (AAPH) [69]. Another study found that MG trapped four peroxyl radicals, with a k_inh of 6.1 × 10⁴ M¹ s¹ in chlorobenzene and 6.0 × 10³ M¹ s¹ in acetonitrile [35]. MG features a bisphenol core with two allylic side chains, and its antioxidant activity is linked to hydroxyl and allyl groups, reinforcing its potential as a therapeutic agent [70]. In aristolochic acid (AA)-induced HK-2 cells, MG (10 μM) decreased oxidative stress and inhibited cell proliferation by obstructing the cell cycle at the G1 phase and preventing G2/M arrest [71]. According to this information, the main effect of MG as an anti-tumor agent is its capacity to protect DNA from oxidation by trapping various radicals.

Bioavailability and pharmacokinetics of magnolol

Bioavailability refers to the amount and percentage of a drug’s original dose that reaches the intended target site or the body fluids where the drug can access its targets [72, 73]. It is essential for pharmacokinetics, which studies how drugs move through the body. ABCD summarizes pharmacokinetics as administration, bioavailability, clearance, and distribution [74]. MG is predominantly absorbed via a lipid-like route in the gastrointestinal system [51].

After oral treatment with 50 mg/kg of MG in rats, MG sulfates and glucuronides were detected in the blood, liver, kidney, brain, lung, and heart. The liver showed the highest levels of MG and MG glucuronides among these organs [75]. Magnolol-2-O-glucuronide, the primary metabolite of MG, was excreted in bile, while MG was eliminated through the digestive tract following oral or intraperitoneal injection. The metabolic products excreted from oral MG in rats included MG (< 90%) and free metabolites (6% glucuronic acid and sulfate) after 1 day of oral administration of MG [76]. The pharmacokinetics of MG were studied with intravenous injection (2 to 10 mg/kg) in rats. The absorption half-life, elimination half-life, maximum concentration, and time to reach maximum concentration were found to be 0.63 h, 2.33 h, 0.16 µg/mL, and 1.12 h, respectively. This study indicated that the oral bioavailability of MG was 4.9%, suggesting poor water solubility and absorption in the gut [77].

Xie et al. indicated that sulfation is essential for magnolol metabolism. Their study identified the sulfated metabolite of magnolol using UPLC-Q-TOF–MS and ¹H-NMR. Magnolol metabolism was investigated in liver S9 fractions from humans (HLS9), rats (RLS9), and mice (MLS9) [78]. The findings indicate that magnolol is metabolized into a mono-sulfated form by SULTs, with SULT1B1 exhibiting the highest sulfation activity. In liver S9 fractions, the sulfation rates of magnolol were similar in HLS9 and RLS9 (0.96 and 0.99 µL/min/mg, respectively) but were lower in MLS9 (0.30 µL/min/mg). Both magnolol and its sulfated metabolite significantly reduced the production of inflammatory mediators (IL-1β, IL-6, and TNF-α) in LPS-stimulated RAW264.7 cells. These results suggest that SULT1B1 is the primary enzyme responsible for magnolol sulfation, and its sulfated metabolite possesses anti-inflammatory effects [79].

Diverse pharmacokinetics studies indicate that various formulations can enhance MG’s bioavailability, including nanoparticles, phospholipid complexes, zinc-based organometallic complexes, liposomes, and emulsions [80]. For example, an in vivo pharmacokinetics study revealed that the formulation of MG in solid dispersions, phospholipid complexes, and solid lipid nanoparticles improved its bioavailability by 1.38, 2.12, and 3.45 times, respectively, compared to MG suspension [80]. Another study in rabbits showed that MG bioavailability increased by 142.8% when combined with PVP (polyvinylpyrrolidone K-30) in an amorphous melting solid dispersion [81]. Finally, a research group demonstrated that lecithin-based mixed polymeric micelles enhance MG’s solubility and bioavailability [82]. The absolute bioavailability for MG after intravenous administration of the formulation was 3.4-fold higher than that of the free compound. MG’s absolute and relative bioavailability for oral administration were 20.1% and 2.9-fold higher, respectively. Therefore, the authors concluded that this formulation had better solubility with suitable physical characteristics, leading to improved bioavailability of MG, which could facilitate its application as a therapeutic agent for treating human cancers. Furthermore, there is potential for research into improving formulations using solid dispersions, phospholipid complexes, and microparticles to enhance bioavailability.

New formulations for the administration of magnolol

Magnolol exemplifies a typical case study of type IV molecules within the biopharmaceutical classification system, characterized by low solubility and low absorption, resulting in very low bioavailability following oral administration. Traditionally, cancer therapies utilize vectorization systems with highly efficient administration routes, preferably parenteral, to optimize the administered dose. Drug carrier systems enhance the stability of the medication, improve pharmacokinetic parameters, and consequently, increase bioavailability [83, 84]. However, this alone is insufficient for cancer therapies; the targeting or specificity of the carrier system is also essential. Specificity is partially achieved through the coupling of ligands on the surface with receptors that are overexpressed in the type of cancer being addressed. Thus, the ligand-receptor attraction will direct the entire carrier system. Based on our review of the literature, there remains limited information on the application of these technologies for MG, suggesting a significant opportunity for exploring new projects to highlight the biological properties of MG.

We are still at an early stage in the study of MG that could revolutionize its more significant impact on the possible treatment of cancer.

Regarding the formulations discussed for MG in the previous section, the solid dispersion with PVP stands out. It is a classic strategy for enhancing solubility in a straightforward and typically economical manner, [79] although it does not provide specificity for cancer treatment. While various types of nanoparticles appear highly promising, their safety aspects are stringent and are generally suitable for high-potency drugs that require a low dose. For natural products with low potency needing a high dose, the delivery system involving different nanoparticles may be insufficient. However, additional concerns arise, as liposomes may significantly raise costs, and SLNs could indicate lower stability. Conversely, there is limited information about the robust performance of niosomes in these applications, and exosomes may prove to be a more suitable system for more specific active ingredients.

However, in regulatory terms, there is more experience in approving liposomes, which could facilitate their manufacture and commercialization.

Preclinical anti-cancer studies

Preclinical studies are essential for cancer research because they provide initial evidence of the safety and efficacy of new drugs before testing in humans. Moreover, they help identify the optimal dose, route, and schedule of administration, as well as potential side effects, toxicity, molecular mechanisms of action and resistance, and interactions with other drugs or biological factors. Additionally, preclinical studies can facilitate the design of clinical trials by offering rational hypotheses, biomarkers, and endpoints for evaluating clinical outcomes. Therefore, these studies are crucial for advancing cancer research and improving cancer care. Since MG has attracted considerable attention for its potential against various types of cancer, we review the latest advances in preclinical studies investigating MG’s anti-cancer properties and mechanisms across different cancer models. By employing in vitro (cell cultures or tissues) and in vivo (animal models or human tumor xenografts) methods, these studies have revealed various mechanisms of anti-cancer effects, such as altering growth, proliferation, signaling, apoptosis, and angiogenesis.

In vitro studies

An in vitro study on the anti-tumor activity of MG against SKOV3 human ovarian and BT474 human breast cancer cells revealed a reduction in the overexpression of the HER2 gene by lowering PI3 K/Akt, along with inhibition of VEGF (vascular endothelial growth factor), MMP2, and cyclin D1 at various concentrations (6.25, 12.5, 25, 50, 100, and 200 µM) [22]. MG was also tested in vitro at concentrations of 1, 5, 10, and 20 µM (IC₅₀ = 5 µM) against human NSCLC cells (NCI-1299) and A549. Results indicated that MG blocked the cell cycle and disrupted the cellular microtubule structures by inhibiting the Akt/mTOR pathway [85].

On the other hand, in human HCT116, SW480, and HEK293 cell lines, MG stimulated the Wnt/β-catenin signaling pathway and β-catenin/T-cell factor-targeted downstream genes. This effect inhibited tumor cell growth and motility at 12.5, 20, 25, 30, 50, and 75 µM [85]. Rasul et al. indicated that MG induced mitochondria-dependent apoptosis while suppressing the PI3 K/Akt pathway. Apoptosis markers such as alterations in the Bax/Bcl-2 ratio, activation of caspase-3, and the induction of autophagy were observed in human gastric adenocarcinoma SGC-7901 cells (at concentrations of MG of 10, 30, 50, 100, 200, and 300 µM) [19]. In another study, human DU145 and PC3 prostate adenocarcinoma cells were incubated with 40 and 80 µM of MG. The study revealed that the compound modulated the cell cycle by downregulating CDK2, CDK4, and pRBp130 expression, followed by increased protein levels of pRBp107 [28].

Similarly, McKeown and Hurta et al. evaluated the in vitro effect of 80 µM of MG on human PC3 and LNCaP cells. The authors found that it reduced the expression of insulin-like growth factor-1 (IGF-1) as well as other related proteins: IGFBP-5, IGFBP-3, IGFBP-4, and the IGF-1 receptor [86]. Additionally, MG inhibited the growth of human lung carcinoma A549 cells by increasing lactate dehydrogenase activity, which facilitated the activation of caspase-3, cleavage of poly-(ADP)-ribose polymerases, and reduction of NF-κB/RelA levels [87]. Finally, a study involving a human breast cancer cell line showed that MG, at concentrations of 10, 20, 30, 40, 50, and 60 µM, prevented the invasiveness of these cells by blocking the NF-κB pathway and suppressing MMP-9 expression [13]. MG has been assessed alongside cisplatin to evaluate its impact on the viability and maintenance of MKN-45 gastric cancer cells. The combined use of MG and cisplatin resulted in a substantial decrease in cell viability and increased Bax expression. Consequently, MG exhibits a significant anti-tumor effect on MKN-45 cells. MG has the potential to help overcome cisplatin resistance when used in conjunction with it in gastric cancer cells [88]. Another study also found that the administration of MG enhanced the effect of cisplatin in reducing cell viability, self-renewal, and invasion activities in cancer stem cells [25]. The administration of MG is not only associated with increased anti-cancer activity of drugs but has also been described as preventing sarcopenia induced by cancer chemotherapy [89]. Consequently, MG shows great promise in boosting the anti-tumor effects of cisplatin.

In vivo studies

In one experiment, tumors were established in nude mice by injecting A549 cells after administering MG at a dosage of 25 mg/kg for 20 days. The compound was shown to reduce tumor sizes and weights compared to the untreated control group [22]. The effects of MG were also studied in female ICR mice during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion, where topical application of 1 and 5 μM of MG for 20 weeks significantly reduced the multiplicity, incidence, and size of papillomas. Furthermore, the authors reported that MG abolished inflammation associated with experimental tumorigenesis, such as the transcriptional activation of iNOS and COX-2 mRNA [90]. Additionally, SK-Hep1/luc2 cells were subcutaneously injected into the right flank of each mouse, followed by gavage administration of 50 or 100 mg/kg of MG for 15 days. The administration of MG diminished the growth and progression of tumors, inducing apoptosis through both extrinsic and intrinsic pathways [57]. According to a study by Li et al. [18], MG demonstrated an effect in both in vitro and in vivo studies on the growth of human gallbladder carcinoma. The mechanisms involved include inducing cell cycle arrest at G0/G1 and apoptosis, along with a significant increase in activated caspase-3. The in vivo study, which utilized GBC-SD cells injected into the left axilla of BALB/c nude mice, showed that MG (5, 10, or 20 mg/kg, i.p. for 28 days) suppressed the growth of xenograft gallbladder cancer tumors in a dose-dependent manner through the induction of apoptosis [18]. In another study, similar in vitro and in vivo effects of MG related to apoptosis induction and increased cleavage of caspase-8 were observed in UVB-induced skin tumor development in SKH-1 mice. This research involved pretreated mice administered 30 and 60 μg of MG before UVB treatments (30 mJ/cm², 5 days/week). Consequently, tumor multiplicity was reduced by 27–55% [30].

In MDA-MB-231 and MCF-7 xenografted murine models, MG (40 mg/kg, i.p. injection) demonstrated an anti-tumor effect, suggesting its potential in breast cancer therapy. MG did not affect body weight or induce visible toxicity in the mice [13]. Another study evaluated the impact of co-treatment with MG and honokiol.

The results indicated that cotreatment inhibited tumor progression and induced apoptosis more efficiently than either honokiol or MG alone. Therefore, the authors suggest combining both compounds (MG with honokiol) may be applied as an adjuvant therapy to improve treatment efficacy of glioblastoma (a malignant brain tumor-associated) [91].

According to the studies described above, a research opportunity exists to evaluate the synergistic effect of MG with other compounds that have demonstrated anti-tumor properties, such as polyphenols [92, 93]. The combined treatment of MG with gemcitabine and cisplatin or gemcitabine significantly reduces body weight loss and skeletal muscle atrophy compared to conventional chemotherapy in mice bearing bladder cancer [94].

Additionally, more studies are necessary to evaluate effective doses and side effects in animal models. Table 1 summarizes the evidence that MG can inhibit cancer cell proliferation and induce cell cycle arrest, autophagy, and apoptosis (discussed in detail in “Preclinical anti-cancer studies” section). We also present some of the molecular pathways involved in the anti-cancer actions of MG, such as PI3 K/Akt/mTOR, MAPK, and NF-κB. It is important to clarify that although preclinical data are promising, human clinical studies are insufficient to draw definitive conclusions (Table 2).

Table 2.

Preclinical anti-cancer studies of magnolol

Type of cancer	Model In vitro using cell lines In vivo using animal models	Concentrations IC50/doses	Mechanism signaling pathways	Results	References
Bladder cancer	In vitro 5637 cells	60 µM (24 h)	Downregulation of Cyclin D1/E/B1, CDK2/4, p-Cdc25c, p-Cdc2, upregulation of p27	Induction of cell cycle at G0/G1 (low and high dose)	[105]
Breast Cancer	In-vitro MCF-7 cell line	58.27 µM (24 h) :53.39 µM (48 h) 49.56 µM	Upregulation of p21, p53, and downregulation of Cyclin B1, CDK1, Upregulation of Bax, Cytochrome C, Cleaved PAR, and downregulation of Bcl-2	Induction of cell cycle arrest and apoptosis	[56]
Colon cancer	In-vitro COLO 205: HT29 COLO 205	3–10 µM (6 days)	Upregulation of p21, and Downregulation of cyclin A/E	Induction of cell cycle arrest at G0/G1	[32]
Gastric cancer	In vitro SGC- 7901	50–100 µM (48 h)	Generates apoptosis Upregulation of cleaved caspase-3 and downregulation of Bcl-2 that inhibit Akt signaling, upregulation of p-PI3 K, p-Akt dependent pathway	Induction of cell cycle arrest at sub-G1 NS	[19]
Prostate cancer	In-vitro Du145; PC3	Du145: ~ 40 µM PC3: ~ 80 µM (24 h)	Downregulation of the protein Cyclin D1	Induction of cell cycle arrest at G0/G1	[28]
Lung cancer	In-vitro H460	80–100 µM (24 h): 60–80 µM (48 h)	Inhibition of PTEN/Akt signaling with upregulation in PTEN and downregulation of P-Akt	Induction of autophagy	[33]
Skin cancer	In vivo TP-induced Carcinogenesis	1–5 µM, twice a week	Downregulation of iNOS, p-p65, p-IκBα, p-ERK, and p-Ak	Inhibition of inflammation, NF-κB signaling, MAPL signaling, and PI3 K/Akt signaling	[90]
Gall bladder cancer	In-vivo BC-SD In-vitro BC-SD,	5–20 mg/kg every day (GBC-SD:20.5) (48 h), 14.9 µM (48 h)	Downregulation of Cyclin D1, Cdc25 A, CDK2 protein levels upregulating by Bax, p53, p21 protein levels and downregulation of Bl-2	Induction of cycle arrest at G0/G1 and apoptosis	[18]
Liver cancer	In-vivo SK-Hep1	P.o. 50–100 mg/kg every day for fifteen days	Downregulation of XIAP, c-P, and Mc1-1 and upregulation of Caspase-3/9 NF-κB activity, p-p65, p-MMP-9, and cyclin	Induction of apoptosis and inhibition of NF-κB signaling	[57]
Lung carcinoma	In-vivo male nude mice	i.p. 25 mg/kg every other day for twenty days	Perturbing the microtubule polymerization	Reduced the tumor sizes and weight	[22]
Breast cancer	In vivo MDA-MB-231 and MCF-7	i.p. 40 mg/kg four times a week for four weeks	Inhibiting MMP-9 through the NF-κB pathway	Suppresses tumor invasion	[13]
Human glioblastomas	In-vivo BALB/cAnN	20 mg/kg/day for 14 days	Reduced p-p38 and p-JNK expression induced autophagy	Induction of apoptosis	[91]
Skin cancer	In-vivo SKH-1 mice	Magnolol pretreated groups 30, 60 μg, 5 days/week for 25 weeks	Enhancing apoptosis, causing cell cycle arrest at G2/M phase	Reduction of tumor multiplicity	[30]

Human clinical studies

Regarding human clinical studies, the search on clinicaltrials.gov, only exposes one Clinical Trial phase III, randomized, double-blind, placebo-controlled, that reports using MG as part of a formulation (Papilocare® Gel) directed to cervical mucosal repair. Specifically, the study focused on the repair of cervical lesions caused by human papillomaviruses. The gel is a mix of hyaluronic acid niosomes, magnolol, honokiol, carboxymethyl beta-glucan, alpha-oligoglycan, coriolus versicolor, neem extract, centella asiatica and Aloe vera. The results of the clinical trial have not yet been disclosed.

Toxicity, side effects, and safety

Toxicity is referred to the degree to which something is detrimental. Before humans use a new compound, it is essential to test its toxicity and ensure that it is safe and effective. This can reveal potential hazards such as causing cancer, damaging DNA, harming the immune system, or affecting reproduction and development. These hazards can lead to severe outcomes for human health and well-being, such as tumors, malformations, sterility, and immune diseases. Thus, testing toxicity is vital to drug development and is mandated by regulatory agencies worldwide. For example, MG, combined with other herbal-medicinal derivative compounds, is a remedy for various disorders, including gastrointestinal anxiety, allergies, and sleeping pills. However, pure combination at high doses has adverse side effects in humans [8].

Thus, MG was tested in an in vivo study to see its toxicity as an isolated compound; human normal hepatocyte U937 and LO2 cells were used to examine toxicity at 10–100 µM concentrations in a dose-dependent manner. According to the authors, concentrations less than 60 µM did not affect the cell survival of U937 cells, while at concentrations below 70 µM, the mortality rate of LO2 cells was less than 20% after 48 h [95]. In contrast, MG at a concentration of 40 µM exhibited cytotoxic effects on VSMCs [96]. Conversely, MG reduced the viability of OC2 cells in a dose-dependent manner (20–200 µM of MG for 24 h) [97]. Interestingly, a study tested MG's ability to prevent UV-induced mutations in Salmonella typhimurium TA102. The authors measured relative mutagenic activities, reflecting the mutation rate of treated cells compared to the mutation rate of control cells multiplied by 100%. The results indicated that MG can effectively prevent UV-induced mutagenesis at low doses (5 µg MG/plate), possibly by removing OH radicals [98]. Notably, while some in vivo studies indicated a slight toxic impact of MG, there is no reported genotoxicity or mutagenic effect [99] for concentrated Magnolia bark extract (> 240 mg/kg) [100]. Similarly, a study involving 40 volunteers who consumed 11.9 mg of MG daily as chewing gum for 30 days did not report any adverse side effects [101]. MG is considered safe in aquaculture due to its potential inhibitory effects against parasitic protozoans (Ichthyophthirius multifiliis) in goldfish [102]. Additionally, it possesses anti-aging, anti-inflammatory, antioxidant, and anti-cancer properties, making it a relevant ingredient in cosmetic products [103]. Therefore, MG appears safe for human administration at low and moderate doses.

Other natural compounds are promising for cancer therapy because they reduce the toxicity produced by synthetic anti-cancer drugs (see for review [104]). However, studies with MG that compare other compounds'toxicity, side effects, and safety are missing. Therefore, this is a research opportunity for researchers focused on the area.

Conclusion and prospects

MG is a natural polyphenolic compound that has demonstrated significant anti-cancer effects through multiple mechanisms, including inhibiting cell proliferation, the promotion of apoptosis, and the suppression of angiogenesis mediated by key signaling pathways. While MG’s low bioavailability and solubility have limited its clinical application, various formulation strategies, including nanoparticles and phospholipid complexes, have been developed to enhance its pharmacokinetics, showing promising results. Regarding safety and toxicity, MG has been tested in vitro and in vivo on different cancer cells and has been used in human clinical trials with no adverse side effects. Despite these advances, a complete understanding of its molecular mechanisms is still lacking, and further research is needed to elucidate its anti-cancer actions fully. This is crucial because despite its potent anti-cancer properties. Additionally, although MG has shown low toxicity and is considered safe at lower doses, there is still a need for more comprehensive clinical trials to confirm its efficacy and safety in human populations. Therefore, while MG holds considerable potential as an anti-cancer agent, further studies are essential to overcome existing challenges, such as improving its bioavailability, detailing the mechanisms in cancer cells that support evidence for antiproliferative activity, and expanding clinical data.

Abbreviations

ABCD

Administration Bioavailability Clearance and Distribution

ADP

Adenosine diphosphate

Akt

Protein kinase B

BT47

Human breast cancerous cell

CDK

Cyclin-dependent kinase

DNA

Deoxyribonucleic acid

ERK

Extracellular signal-regulated kinase

HER2

Human epidermal growth factor receptor 2

HIF 1α

Hypoxia-inducible factor 1alpha

HL60

Human promyelocytic leukemia cells

lbMPS

Lecithin-based-mixed-polymeric micelle

IC₅₀

Inhibition concentration

IGF

Insulin like growth factor

IGFBP

Insulin-like growth factor binding protein

i.p.

Intraperitoneal

IUPAC

International Union of Pure and Applied Chemistry

LO2

Human fetal hepatocyte line

MAPK

Mitogen-activated protein kinase

MBE

Magnolia Bark Extract

MAPK

Mitogen-Activated Protein Kinase/Extracellular signal-regulated kinases

MAPK/ERK

Mitogen-activated protein kinases

MCF-7

Michigan Cancer Foundation-7

MCF-10 A

Mammary epithelial cell line

MG

Magnolol

mM

Millimolar

µM

Micromolar

MMP2

Matrix metalloproteinase 2

MMP-9

Matrix metalloproteinase-9

MOLT-4

Human acute lymphoblastic leukemia cell line

mTOR

Mammalian target of rapamycin

mTORC1

MTOR complex 1

NA

Not applicable

NaDOC

Sodium deoxycholate

NSCLC

Non-Small Cell Lung Cancer

NF-κB

Nuclear factor-KappaB

NSCLC

Non-small cell lung cancer

OC2

Organ of Corti 2 (cell number)

PC-3

Prostate Cancer cells

PI3 K

Phosphoinositide 3-kinase

PIP3

Phosphatidylinositol (3,4,5)-triphosphate

SKVO3

Human ovarian cancer cell

VEGE

Vascular endothelial growth factor

VSMCs

Vascular smooth muscle cells

4E-BP1

4E binding protein 1

Author contributions

AR, NG, DK, LE.P–C, SI.P–C, HC, AA, GL-G, YU, SH, LK, JS-R made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas that is, revising or critically reviewing the article; giving final approval of the version to be published; agreeing on the journal to which the article has been submitted; and confirming to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.