Future Medicinal Chemistry

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Advances in antitumor effects of pterostilbene and its

derivatives

Xin Yu, Mengzhen Xu, Ziye Gao, Haixing Guan & Qingjun Zhu

To cite this article: Xin Yu, Mengzhen Xu, Ziye Gao, Haixing Guan & Qingjun Zhu (2025)
Advances in antitumor effects of pterostilbene and its derivatives, Future Medicinal Chemistry,
17:1, 109-124, DOI: 10.1080/17568919.2024.2435251

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FUTURE MEDICINAL CHEMISTRY
2025, VOL. 17, NO. 1, 109–124
https://doi.org/10.1080/17568919.2024.2435251

REVIEW

Advances in antitumor effects of pterostilbene and its derivatives

Xin Yua*, Mengzhen Xua*, Ziye Gaoa, Haixing Guanb,c and Qingjun Zhua
a
Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China; bExperimental Center,
Shandong University of Traditional Chinese Medicine, Jinan, China; cKey Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of
Education, Shandong University of Traditional Chinese Medicine, Jinan, China

ABSTRACT ARTICLE HISTORY

Pterostilbene (PT) is a naturally occurring small molecule stilbenoid that has garnered significant Received 28 February 2024
attention due to its potential therapeutic effects in tumor diseases. In this review, we conducted Accepted 20 November
a comprehensive analysis of the antitumor effects of PT and its derivatives on various cancer types, 2024
including colon, breast, liver, lung, and pancreatic cancers in recent 20 years. We have succinctly
KEYWORDS
summarized the PT derivatives that exhibit superior anti-tumor efficacy compared to PT. Additionally, Pterostilbene; pterostilbene
we reviewed the potential structure-activity relationship (SAR) rules and clinical application methods to derivatives; antitumor effect;
establish a foundation for chemical modification and clinical utilization of stilbene compounds. structure-activity
relationships; stilbenes

1. Introduction
a dosage of 3,000 mg/(kg-d) in animals did not result in any
Pterostilbene (PT) is a naturally derived small molecule, earn­ significant toxic side effects [7]. Due to its remarkable biologi­
ing its name from its initial discovery in Pterocarpus marsu­ cal activity and promising medicinal value, PT has emerged as
pium heartwood. It can also be found in various plant sources a prominent focus in cancer therapy research.
including blueberries, grapes, and palmetto. Functioning as PT (3, 5-dimethoxy-4’−hydroxy stilbene) is
a botanical antitoxin, it exhibits protective properties against a representative member of the stilbene family, as depicted
diverse external factors such as ultraviolet radiation and in Figure 1. Studies have shown that the stilbene structure
pathogenic invasions [1]. Based on reported experimental exhibits notable antitumor effects. Combretastatins, a class
evidence, PT exhibits potential therapeutic effects in cancer of stilbenes, have been extracted from Combretum afrum
prevention and treatment, inflammatory skin diseases, regula­ (Eckl. & Zeyh.) Kuntze and include compounds such as
tion of blood sugar and lipid levels, cardiovascular disease A1–5, which feature a cis-configuration and have demon­
management, aging intervention, as well as enhancement of strated anticancer properties. Compounds of this class have
memory and cognition [2]. Cancer refers to a malignant tumor. been considered in anticancer clinical trials, indicating their
According to the latest global cancer statistics report released potential therapeutic value in oncology. Trans-resveratrol
by the International Agency for Research on Cancer (IARC), it is and other natural trans-stilbenoids, such as PT, are known
estimated that there will be approximately 28.4 million new for their outstanding antitumor effects; however, their clin­
cancer cases worldwide by 2040 [3]. Numerous studies have ical application is impeded by limited bioavailability, which
demonstrated the potential of PT to impede cancer cell hinders their broader use in medicine. Compared to resver­
growth and proliferation, induce apoptosis, and halt cancer atrol, the substitution of the two hydroxyl groups in the left
progression [4–6]. In terms of safety, administration of PT at ring with methoxy groups resulted in a significant

CONTACT Qingjun Zhu [email protected] Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese
Medicine, No. 16369 Jingshi Road, Changqing District, Jinan City, Shandong Province 250355, China
*
Xin Yu and Mengzhen Xu contributed equally to this work.
© 2024 Informa UK Limited, trading as Taylor & Francis Group
110 X. YU ET AL.

potent antitumor activity in colon cancer cell lines HT-29,

Article highlights Caco-2, and HCT116 by modulating the p38/MAPK pathway
● Stilbene structure is one of the most important anticancer and PI3K/Akt pathway, as well as suppressing colon inflamma­
pharmacophores. tion through inhibition of iNOS and COX-2 expression
● The comparative analysis of the anti-cancer pharmacological activity (Figure 2). These findings suggest that PT derivatives hold
and mechanism of pterostilbene and its derivatives in various types of
cancer is presented. promise as potential therapeutic agents for inhibiting further
● PT and its derivatives against colon cancer progression of colon cancer.
● PT and its derivatives against breast cancer
● PT and its derivatives against liver cancer
● PT and its derivatives against lung cancer 2.1. PT against colon cancer
● PT and its derivatives against pancreatic cancer
● The structure-activity relationship analysis of pterostilbene and its Excessive production of nitric oxide has been implicated in the
derivatives with diverse modified architectures is discussed.
● Modification based on carbon-carbon double bonds pathogenesis of colonic mucosal and tissue damage, thus
● Modification based on benzene ring substitutions aggravating the inflammatory cascade. Consequently, effica­
cious 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 atte­
nuated the activation of nuclear factor-κB (NF-κB) by inhibiting
the phosphorylation of protein kinase C-β2 (PKC-β2), subse­
quently resulting in a reduction in the expression of down­
stream 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)
Figure 1. Chemical structure of pterostilbene. 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-
enhancement of both bioactivity and bioavailability of PT. and time-dependent reduction in the proliferation rate of
This discovery serves as a source of inspiration for us to Caco-2 and HT-29 cells upon treatment with PT, accompanied
modify the structure based on PT and systematically investi­ by a decrease in the number of G2/M phase cells and an up-
gate the potential SAR, thereby facilitating the exploration of regulation of p21 expression (Table 1). The antiproliferative
derivatives with enhanced research value and medicinal and cytotoxic effects of PT were potent, potentially exerted
potential in future studies. through the regulation of the STAT3 and AKT kinase signaling
In this review, we present a comparative analysis of the phar­ pathways [12,13]. Furthermore, PT effectively suppressed col­
macodynamics and pharmacological effects of PT and its deriva­ ony formation in human colon cancer cells including Caco-2,
tives across various cancer types, encompassing colon, breast, HT-29, and HCT-116. The sensitivity to PT and resveratrol
liver, lung, and pancreatic cancers. In order to provide treatment varied among these cell lines with the highest
a comprehensive and systematic description of the antitumor response observed in Caco-2 followed by HT29 and HCT116;
effects of PT and its derivatives, we have carefully selected relevant notably, PT exhibited superior inhibitory effects compared to
references from the past two decades. Additionally, we discuss the resveratrol across all three cell types (IC50 values for PT: Caco-
SAR between PT and derivatives with various modified structures, 2: 75 µM; HT29: 15 µM; HCT116: 12 µM) [14,15]. Paul et al., in
thereby establishing a fundamental basis for the chemical mod­ their study on HT-29 cells, demonstrated that PT effectively
ification and clinical application of stilbene compounds. suppressed cell proliferation by down-regulating c-Myc
expression and cyclin D1 levels, while simultaneously increas­
ing cleaved PARP levels. Furthermore, PT exhibited inhibitory
2. Colon cancer
effects on iNOS and COX-2 expression through the regulation
Colon cancer is a prevalent gastrointestinal malignancy pri­ of the p38 mitogen-activated protein kinase (MAPK) pathway.
marily affecting the colon region. Minimally invasive endo­ Additionally, PT modulated detoxification enzyme levels such
scopic procedures are effective in treating early-stage cases, as glutathione transferase to enhance carcinogen excretion
while late-stage treatment necessitates a comprehensive and prevent colon carcinogenesis [16–18].
approach encompassing surgery, chemotherapy, immunother­
apy, traditional Chinese medicine, and other supportive thera­
2.2. PT derivatives against colon cancer
pies [8]. The inhibitory effects of PT on azoxymethane-induced
colonic abnormal crypt foci (ACF) and colonic tumors have Cheng et al. discovered that 3’-hydroxypterostilbene exhibits
been demonstrated. Moreover, PT and its derivatives exhibit potential anti-colon cancer properties. In nude mice bearing
 FUTURE MEDICINAL CHEMISTRY 111

Figure 2. Schematic representation of antitumor effects of pterostilbene and its derivatives on colon cancer, breast cancer, liver cancer, lung cancer and pancreatic
cancer.

COLO205 tumor xenografts, intraperitoneal injection of 3’- Resveratrol :78 ± 4), and its benzylated analogue possessed
hydroxypterostilbene (10 mg/kg i.p.) resulted in the down- K-Ras inhibitory effects in HCT-116 colon cancer cells [22].
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 3. Breast cancer
superior IC50 values compared to PT in COLO205, HCT-116, and
Breast cancer is a prevalent malignancy in women, with its
HT-29 cells (IC50 values for 3’-hydroxypterostilbene derivatives:
incidence rate steadily increasing over the years. Among the
9.0 ± 0.2, 40.2 ± 0.6, 70.9 ± 1.0; PT: 33.4 ± 0.2, 47.1 ± 0.6, 80.6 ±
various types of breast cancer, triple-negative breast cancer is
3.3). In COLO205 cells, 3’-hydroxypterostilbene was observed to
referred to as the “monarch” due to its unfavorable prognosis,
decrease the phosphorylation of p38 MAPK and PI3K/Akt/mTOR/
heightened risk of distant metastasis, and substantial propor­
p70S6K while activating the ERK1/2 and JNK1/2 MAPK pathways
tion of proliferating cancer cells. Currently, there are no estab­
in a time-dependent manner. The results of this study suggest
lished treatment guidelines for triple-negative breast cancer
that 3’-hydroxypterostilbene exhibits a higher potency in indu­
[23]. The PT and its derivatives exhibit promising potential as
cing autophagy compared to PT in COLO205 cells [19].
anti-breast cancer agents, demonstrating efficacy against tri­
González-Sarrías et al. investigated the IC50 values of gut
ple-negative breast cancer cells, MCF-7 cells, and stem cells.
microbiota metabolites of PT in Caco-2 cells and observed that
Their primary mechanisms of action involve the modulation of
4-hydroxystilbene, exhibiting the lowest IC50 value (Table 1),
key pathways including JAK/STAT3, wnt/β-linker, NF-κB/
demonstrated superior antiproliferative activity compared to
miR488, PI3K/Akt/mTOR signaling cascades, along with the
PT. Furthermore, it was discovered that the differential meta­
regulation of genes associated with tumorigenesis (Figure 2).
bolizing ability of these compounds may account for PT’s
heightened sensitivity toward Caco-2 cells as opposed to HT-
29 cells [20].
3.1. PT against breast cancer
Pinostilbene, the main metabolite of PT in the colon, was
derived by Sun et al., who demonstrated that it induced Among the various subtypes of human breast cancer cells, exten­
S-phase cell cycle arrest at concentrations of 20 and 40 μM sive research has been conducted on the anticancer efficacy of
and significantly suppressed the growth of HT-29 and HCT-116 PT specifically in MCF-7 cells. It has been experimentally demon­
cells [21]. strated that PT effectively induces apoptosis in MCF-7 cells. On
Grau et al. modified the stilbenes’ structure through alkylation one hand, PT upregulates mitochondrial apoptotic signals, such
or acylation of hydroxyl groups and assessed their IC50 values in as Bax and a series of cysteine aspartic enzymes, thereby indu­
HT-29 cells. The 2-arylindole analogue (Table 1) exhibited higher cing cysteine aspartase-dependent apoptosis through increased
cytotoxicity compared to resveratrol (IC50 value of 10 ± 2; activation of downstream effectors prompted by elevated
112 X. YU ET AL.

Table 1. PT and its derivatives in colon cancer cells: dose and effects.
Cancer type Models Compound Dose Anticancer Effect Reference
Colon HT29 cells Pterostilbene 0,5,10,25,40,50,60,75,100 µM(48,72 h) Inhibition of proliferation, G1 cell [12]
cancer arrest, and/or triggering apoptosis
IC50 values of 45.1 ± 13.7 µM (48 h);
37.9 ± 5.4 µM (72 h)
Unclear IC50 values of : 10 ± 2 µM; Resveratrol [22]
:78 ± 4 µM

Caco-2 cells Pterostilbene 5–100 μM (48,72 h) Significant dose-dependent [15]

antiproliferative and cytotoxic
effects
IC50 values of 67.6 ± 12.3 µM
（48 h）; 43.0 ± 11.6 µM (72 h)
0.78–100 μM(48,72 h) IC50 values of 34.0 ± 8.1 μM [20]
(48 h);24.4 ± 11.3 μM (72 h)

COLO205 cells 5–100 μM (24 h) IC50 values of 9.0 ± 0.2，40.2 ± 0.6， [19]
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）

superoxide anion levels and mitochondrial depolarization [24– regulating EMT of triple-negative breast cancer cells through up-
26]. On the other hand, PT enhances tumor necrosis factor- regulation of microRNA-205, possibly via modulation of the Src/
related apoptosis-inducing ligand (TRAIL)-induced apoptosis by Fak signaling pathway [38]. The activity of MMP-2 and MMP-9, as
activating the reactive oxygen species (ROS)-mediated CHOP well as the migration of triple-negative breast cancer cells, were
pathway [26,27]. Additionally, PT has been shown to impede also suppressed by PT through inhibition of NF-κB-mediated
MCF-7 cell proliferation through the modulation of the wnt/β- expression of urokinase-type fibrinogen activator, invasive foot-
linker pathway and suppress EMT- and HRG-β1-induced cellular related protein, and Rac1/WAVE-2/Arp2/3 pathway [39,40].
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
3.2. PT derivatives against breast cancer
cells can be achieved through combination therapy with tamox­
ifen or by utilizing zein nanocomposites as carriers [31,32]. PT can Van den Brand et al. reported that 2,3‘,4,5’-tetramethoxy-trans-
also induce autophagy, which exhibits cytoprotective effects, stilbene (Table 2) activated the aryl hydrocarbon receptor AHR
thereby suggesting its potential clinical application in combina­ (with an EC50 value of 2.0 μM) and induced AHR-mediated
tion with autophagy inhibitors [29]. Chakraborty et al. reported cytochrome P450 1A1 (CYP1A1) activity (with an EC50 value of
that the growth arrest observed in MCF-7 cells might be linked to 0.7 μM), while also exhibiting greater efficacy in reducing via­
the induction of cellular autophagy and a transformation toward bility and migration of MCF-7 cells compared to PT and resver­
an epithelioid cell-like phenotype, as demonstrated by their atrol. The derivative exhibited selective inhibition of the G1
study [33]. phase in the MCF-7 tumor cell cycle, while leaving the cell
The proliferation and migration of triple-negative breast can­ cycle status unaffected in the non-tumorigenic epithelial cell
cer cells were effectively inhibited by PT. Wakimoto et al. demon­ line MCF-10A cells. Interestingly, this study represents
strated the high sensitivity of PT in suppressing the growth of a pioneering demonstration that this compound selectively
triple-negative breast cancer cells [34]. PT suppressed the prolif­ targets breast cancer cells without impacting non-
eration of triple-negative breast cancer cell by inhibiting the tumorigenic cells. Cell type-specific differences may arise due
expression of cMyc and human telomerase reverse transcriptase to variations in the AHR ligand binding pockets, distinct
(hTERT) expression, down-regulating mutant p53, cell cycle pro­ recruitment of co-activators/repressors, and cell-type specific
tein D1, mammalian target of rapamycin (mTOR), and β-linker expression patterns, as well as differential availability of ligand
protein expression [35,36]. The underlying mechanism may DNA recognition sites among the investigated cell lines [41].
involve the JAK/STAT3 signaling pathway [37]. Su et al. demon­ The current focus in the field of epigenetic cancer research
strated the anti-metastatic potential of PT in vitro and in vivo by lies in addressing hypermethylation of tumor suppressor genes
 FUTURE MEDICINAL CHEMISTRY 113

Table 2. PT and its derivatives in breast cancer cells: dose and effects.
Cancer
type Models Compound Dose Anticancer Effect Reference
Breast MCF-7 cells Pterostilbene 0–150 μM Inhibition of Wnt signaling, cell cycle arrest and [29]
cancer (24,48,72 h) apoptosis
0–30 μM (10 days) Inhibition of cell activity and migration, cell cycle [41]
shift, activation of AHR and EROD activities
IC50 values of 3.6 μM; PT: 15.6 μM

Triple-Negative Breast Pterostilbene Unclear Inhibition of MDA-MB-231 cell proliferation and [34,38]
Cancer Cells migration
0–1000 μM (3 High ratio of renilla luciferase and Wnt IC50 values [46]
days) (5.1 ± 0.6 μM)

BCSC cells Pterostilbene Unclear Inhibition of M2 tumor-associated macrophage [47]

(TAM)-induced BCSC proliferation and metastasis
Unclear Inhibition of mammosphere formation, reduction of [49,50]
BCSC markers such as acetaldehyde
dehydrogenase (ALDH) and CD44 levels, and
modulation of various stem cell maintenance
pathways

and hypomethylation of genes associated with cancer- containing PT and resveratrol with the enzymatic secretome
promoting functions. Lubecka et al. have successfully identified, derived from the gray mold fungus. Interestingly, they identified
for the first time, a comprehensive genome-wide landscape several structurally distinct derivatives that exhibited specific
responsive to resveratrol-induced DNA methylation. They inhibition of the Wnt pathway in triple-negative breast cancer
demonstrated that stilbene compounds target key regulators cells (Table 2). It was observed that these derivatives effectively
of cancer signaling pathways and methylated genes associated suppressed Wnt activity and impeded β-linker accumulation in
with oncogenic and pro-metastatic functions, resulting in the both the cytoplasm and nucleus by disrupting nuclear effectors
epigenetic silencing of MAML2 and the subsequent inactivation downstream of the disruption complex [46].
of NOTCH signaling [42]. Subsequently, Beetch et al. conducted The proliferation and metastasis of breast tumor stem cells
genome-wide DNA methylation analyses to investigate the (BCSCs) induced by M2 tumor-associated macrophages (TAMs)
modified response profile to stilbenes, revealing dynamic inter­ can be effectively inhibited by PT through modulation of EMT-
actions between DNA and DNMT3A and NF1C transcription related signaling pathways, particularly the NF-κB/miR488
factors. Additionally, they elucidated the mechanism of pathway [47]. Certain phytochemicals (Table 2), akin to PT,
DNMT3B-dependent hypermethylation and silencing of OCT1- can also target BCSC and suppress tumors by inhibiting mam­
targeted oncogenes. It was observed that PT derivatives could mosphere formation, reducing levels of BCSC markers such as
induce alterations in the epigenetic marks within the oncogene acetaldehyde dehydrogenase (ALDH) and CD44, and modulat­
enhancer region of breast cancer cells [43–45]. These findings ing various stem cell maintenance pathways [48–50].
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
4. Liver cancer
breast cancer progression through gene targeting.
Huber et al. synthesized a total of 73 dimeric stilbene analo­ Liver cancer exhibits a high incidence and mortality rate, while
gues through the biotransformation reaction of a mixture its advanced treatment yields a low cure rate due to the
114 X. YU ET AL.

dissemination of cancer cells [51]. PT has been shown to gene expression [60]. Qian et al. discovered that PT effectively
impede the proliferation and migration of liver cancer cells, suppressed motility and invasion in human liver cancer cells by
induce apoptosis, and its derivatives can inhibit the growth of down-regulating metastasis-associated protein 1 (MTA1) [56].
HepG2 cells. The main mechanisms involved in regulating Furthermore, the combination of PT with curcumin and its ana­
these effects include modulation of the PTEN/Akt pathway logues targeting lysyl oxidase demonstrated noteworthy antitu­
and AMPK signaling pathway, as well as suppression of mor metastatic activity, warranting further investigation [61].
MAT1 expression and MMP-9 activity (Figure 2). These findings Tzeng et al. revealed that under hypoxic conditions following
hold significant implications for liver cancer research. catheter artery chemoembolization treatment, nanoparticles of
PT exhibited enhanced cytotoxicity compared to PT alone.
Moreover, these nanoparticles effectively suppressed the expres­
4.1. PT against liver cancer sion of hypoxia and apoptosis-associated proteins, thereby miti­
The proliferation of liver cancer cells was inhibited and apop­ gating tumor invasion and metastasis [62].
tosis 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 4.2. PT derivatives against liver cancer
pathway through upregulation of p53 expression and down­
regulation of superoxide dismutase 2 (SOD2) expression. This Hasiah et al. investigated the SAR between cytotoxicity and
led to a dose-dependent inhibition of tumor growth in diethyl­ antioxidant activity of six methoxylated stilbene analogues in
nitrosamine plus carbon tetrachloride-induced hepatocellular HepG2 cells, employing MTT assay for cytotoxicity evaluation
carcinoma mice, as well as a dose-dependent reduction in and trivalent ferric reducing antioxidant power (FRAP) assay
viability of HepG2 cells. Furthermore, this treatment induced for measuring antioxidant activity. The concentration-
apoptosis without exhibiting genotoxic activity [52,53]. The dependent cytotoxicity and antioxidant activity of the stilbene
Ribonucleotide reductase M2 (RRM2) protein plays a pivotal analogues were observed, with (Z)-3,4,4’-trimethoxystilbene
role in DNA synthesis and repair, thereby facilitating cellular (Table 3) exhibiting the highest potency and selectivity as an
proliferation while suppressing apoptosis. Wang et al. demon­ antiproliferative agent in HepG2 cells (with an IC50 of 89 µM),
strated that PT exhibited a potent inhibitory effect on the while also demonstrating the most pronounced antioxidant
activity of RR enzyme in vitro through its specific targeting activity across all concentrations [63]. The discovery of these
of RRM2 (with an IC50 value of approximately 0.62 μM). findings presents novel perspectives for the investigation of
Notably, this inhibitory potency surpasses that of currently PT derivatives.
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 5. Lung cancer
activating the PTEN/Akt pathway. Moreover, it exerts inhibi­
tory effects on cell proliferation and induces apoptosis in Lung cancer is a malignancy characterized by a high global
tumor cells by downregulating HDAC1 and HDAC2 while incidence and mortality rate. It encompasses two fundamental
upregulating acetylated p53 [55–57]. Dewi et al. demonstrated subtypes: small cell lung cancer (SCLC), which represents
that PT effectively suppresses the proliferation of AH109A cells a minority of cases and is primarily managed through systemic
by inducing cell cycle arrest at the G0/G1 phase, exhibiting chemotherapy in combination with radiotherapy and surgery;
a dose-dependent reduction in the expression of cyclin- non-small cell lung cancer (NSCLC), comprising adenocarcinoma,
dependent kinases 4/6 (CDK4/6), and elevating intracellular squamous cell carcinoma, and large cell carcinoma, predomi­
peroxide levels [58]. Furthermore, Lee et al. demonstrated nantly treated using surgical interventions [64]. The PT and its
that PT could effectively prevent the enrichment of CD133(+) derivatives exhibit promising inhibitory effects on lung disease-
liver cancer CSCs, suppress tumor sphere formation, and associated tumors both in vivo and in vitro. Their main mechan­
downregulate stemness gene expression [59]. isms involve the regulation of the Notch1 signaling pathway, AKT
PT exhibits inhibitory effects on the migration and invasion of and JNK pathways, as well as modulation of cell proliferation and
liver cancer cells. Pan et al. demonstrated that PT effectively apoptosis through P53 and COX-2 regulation (Figure 2). These
suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)- findings highlight their potential as therapeutic agents for lung
induced migration in HepG2 cells by downregulating MMP-9 cancer, warranting further comprehensive investigations.

Table 3. PT and its derivatives in liver cancer cells: dose and effects.
Cancer
type Models Compound Dose Anticancer Effect Reference
Liver HepG2 Pterostilbene 0,12.5,25,50,100 µM (24 h) Concentration-dependent decrease in cell viability and [53]
cancer cells proliferation
3.125–100 µM (24 h) Inhibited cell proliferation (IC50 values of 89 μM) with [63]
significant antioxidant activity at all concentrations
 FUTURE MEDICINAL CHEMISTRY 115

5.1. PT against lung cancer as well as the activation of Extracellular regulated protein
kinases 1/2 (ERK1/2). Moreover, their study revealed that pre-
Chen et al. demonstrated that PT significantly attenuated
treatment combined with autophagy inhibitors, such as
tumor heterogeneity, reduced tumor volume, and suppressed
3-methyladenine and bafilomycin A1, effectively enhanced
tumor burden in ethyl carbamate-induced lung tumors in
apoptosis in docetaxel-induced multidrug-resistant human
mice by inhibiting the epidermal growth factor receptor
lung cancer cell lines [74]. Mena et al. discovered that lysoso­
(EGFR) and its downstream signaling pathways [65].
mal membrane permeabilization serves as the primary
Furthermore, Ma et al. demonstrated that PT effectively sup­
mechanism of cell death induced by PT. A375 melanoma
pressed tumor growth in PC9 ×enografts in thymus-free nude
and A549 lung cancer cells with low levels of HSP70 showed
mice by activating the endoplasmic reticulum stress (ERS)
high susceptibility to PT, whereas HT29 colon and MCF7 breast
signaling pathway and promoting apoptosis-related protein
cancer cells with higher levels of HSP70 were more resistant
expression. Notably, these effects were synergistically
[75]. The presence of PT in NSCLC cells resulted in the aug­
enhanced by Mediterranean flavin [66]. Surien et al. found
mentation of endoplasmic reticulum stress signals, namely
that PT significantly up-regulated p53, p21 and p27 protein
PERK, IRE1, ATF4, and CHOP. Consequently, this led to an
expression as well as the p53/p21 pathway in an N-nitroso-
upregulation of ROS levels, a downregulation of intracellular
trichloroethylurea (NTCU)-induced squamous cell carcinoma
glutathione levels, induction of apoptosis and inhibition of cell
(SCC) Balb/C mouse model of the lung. This led to cell cycle
viability. This regulatory mechanism is potentially associated
arrest and inhibited the progression of precancerous lesions
with COX-2 [66,76]. In human lung adenocarcinoma cells, PT
by reducing the thickness of bronchial epithelium [67,68].
modulated the apoptotic index and reactive oxygen species
PT has been demonstrated to induce cellular senescence and
levels by regulating Notch1 signaling pathway transmission,
inhibit cell proliferation in lung cancer cells. Tippani et al.
mitochondrial membrane potential, and intracellular glu­
reported significant telomerase inhibition, anti-mitotic activity,
tathione content [77].
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 discov­
ered that PT can effectively inhibit telomerase activity, induce the 5.2. PT derivatives against lung cancer
DNA damage response, and significantly decrease cell viability in
a concentration- and time-dependent manner. Ultimately, it ivative 4,4’-(ethane-1,2-diyl) bis (2-methoxyphenol) (Table 4)
leads to cellular senescence through a p53-dependent pathway exhibited a high-affinity interaction with an Akt molecule at
[70,71]. Lee et al. demonstrated the essential role of p53 in the both the ATP-binding and allosteric sites. Moreover, it signifi­
mechanism of PT action. They observed that PT induced activa­ cantly reduced cell viability (IC50 of 108.6 ± 10.82, 103.5 ± 6.08,
tion of ATM and CHK1/2 upstream of p53 in two precancerous and 138.3 ± 25.63 μM) and colony formation in NSCLC (A549,
human bronchial epithelial cell lines, HBECR and HBECR/p53i, H23, and NCI-H460), suggesting its potential as an Akt inhibi­
leading to a more potent inhibition of cell cycle progression tor. The treatment also demonstrated a dose-dependent
and p53-dependent cell proliferation [72]. Additionally, Huang increase in the apoptosis rate of A549 cells, with percentages
et al. demonstrated that PT treatment resulted in the down- of 23.25%, 61.26%, and 86.30% observed at concentrations of
regulation of MUC1, NF-κB, CD133, β-catenin, and transcription 10, 100, and 200 μM, respectively [78].
factor SOX2 expression and exhibited a dose-dependent inhibi­ Stilbenes exert an impact on gefitinib resistance in NSCLC
tion of CSC proliferation [73]. cells. Lu et al. discovered that trans-3,5,4’-trimethoxystilbene
PT can induce apoptosis and autophagy in lung cancer (Table 4) effectively inhibited the MAPK/Akt/Bcl-2 pathway by
cells. Hsieh et al. demonstrated that PT treatment induced upregulating the expression of miR-345 and miR-498, thereby
autophagy through the inhibition of AKT and JNK pathways, enhancing sensitivity to gefitinib and inducing apoptosis [79].

Table 4. PT and its derivatives in lung cancer cells: dose and effects.
Cancer
type Models Compound Dose Anticancer Effect Reference
Lung A549 Pterostilbene Unclear Regulated NSCLC cell proliferation and apoptosis via targeting [66,76]
cancer Cells COX-2
0–200 µM (24 h) Inhibited cell proliferation and induced apoptosis [78]
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

PC9 Pterostilbene Unclear Elimination of Osimertinib resistance [123]

cells 0–500 µM(24,48 h,72 h) IC50 values of 45.64 ± 2.06 µM(24 h);56.78 ± 1.97 µM [79]
(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)
116 X. YU ET AL.

6. Pancreatic cancer modulated gene expression in PANC-1 cells, upregulated the

antiproliferative markers cytochrome C, Smac/DIABLO, and
Pancreatic cancer is considered one of the malignancies with
MnSOD/antioxidant activity, and suppressed STAT3 phosphory­
the most unfavorable prognosis, characterized by insidious
lation. Furthermore, oral administration of PT effectively inhib­
and atypical clinical manifestations. Its diagnosis and treat­
ited tumor growth [86].
ment 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 6.2. PT derivatives against pancreatic cancer
immense clinical significance [80]. PT and its derivatives exhi­
bit potent antiproliferative activity against pancreatic cancer Florio et al. demonstrated that the modified PT derivative
by down-regulating the RAGE/STAT3 signaling pathway, ren­ (Table 5) exhibited enhanced efficacy in suppressing clono­
dering them promising candidates for intensive investigation genicity and inhibiting colony formation in pancreatic cancer
as therapeutic agents in the management of this malignancy cell lines, achieved by preserving the 4′-phenol moiety while
(Figure 2). introducing various substituents at para- or neighboring posi­
tions 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
6.1. PT against pancreatic cancer cancer cells. Furthermore, the introduction of methyl substitu­
The Pancreatic Ductal Adenocarcinoma (PDAC) constitutes tions enhanced lipophilicity and stability in human plasma,
80–90% of pancreatic malignancies and represents one of thereby facilitating improved gastrointestinal tract penetra­
the most lethal neoplasms [81]. Hsu et al. demonstrated that tion, selectivity, and antiproliferative capacity [87].
PT effectively suppressed cell proliferation, induced apoptosis Grau et al. synthesized a series of stilbene analogues and
and autophagy, and down-regulated the expression of multi­ observed their antitumor effects in MIA PaCa-2 cells. Among
drug resistance protein 1 (MDR1) by targeting the RAGE/PI3K/ these analogues, PT derivatives (Table 5) exhibited the most
Akt signaling pathway in PDAC cells, thereby enhancing che­ potent cytotoxicity with IC50 values of 28 ± 4 μM [22].
mical sensitivity [82]. Chen et al. discovered that PT could
enhance anticancer effects in combination with the autophagy
7. Antitumor SAR of PT derivatives
inhibitor chloroquine, as evidenced by their ability to down-
regulate the RAGE/STAT3 signaling pathway and inhibit pan­ The stilbenoid PT is a naturally occurring compound, charac­
creatic cancer growth and tumor autophagy in an in-situ terized by the dominant presence of trans-stilbene in its
animal model [83]. structure. Variations among natural stilbenoids primarily arise
The proliferation of the PANC-1 pancreatic cancer cell line was from differences in the type and number of substituents on
effectively inhibited by PT treatment. In the PANC-1 pancreatic the benzene ring, with hydroxyl and methoxy substitutions
cancer cell line, PT effectively suppressed mitochondrial mem­ being more prevalent [88]. Hydroxyl groups replace hydrogen
brane depolarization and activation of effector cysteine aspara­ at the 3,5,4’ positions in natural stilbenoids compounds such
ginase, leading to a concentration- and time-dependent as resveratrol. Isothapontigenin replaces the hydrogen atom
reduction in cell viability. Moreover, PT induced S-phase cell- at position 3’ of resveratrol with a methoxy group. Gnetol
cycle arrest, apoptosis, and autophagy [82,84]. Kostin et al. involves the substitution of hydroxyl groups at positions 3, 5,
demonstrated a synergistic antiproliferative effect of PT in com­ and 2‘,6.’ The naturally occurring stilbenoids were insufficient
bination with epigallocatechin gallate (EGCG, Table 5) on the to meet the demand for their pharmacological activity in
PANC-1 cell line [85]. The antiproliferative effect of PT was initially humans. To enhance the chemopreventive and/or therapeutic
demonstrated by McCormack et al., who observed that PT effects of cancer, chemists have introduced various groups

Table 5. PT and its derivatives in pancreatic cancer cells: dose and effects.
Cancer
type Models Compound Dose Anticancer Effect Reference
Pancreatic PDAC cells Pterostilbene 0–75 μM (48,72 h) Inducing S-phase cell cycle arrest, apoptosis, and [82,83]
cancer autophagic cell death and inhibiting multidrug
resistance protein 1 (MDR1) expression
Unclear IC50 values of 28 ± 4 µM; Resveratrol :132 ± 6 µM [22]

AsPC1, BxPC3, 0–100 μM(72 h) IC50 values of 14.72 μM; 22.70 μM;27.75 μM; [87]
and Capan2 Resveratrol:29.01 μM;48.73μ; >100 μM (in AsPC1,
cells BxPC3, and Capan2 cells)
 FUTURE MEDICINAL CHEMISTRY 117

such as isopentenyl, aminomethyl, phosphoric acid, glycoside, depolymerization activity. Moreover, pyrazoline derivatives
amide, etc., into the stilbenoid nucleus of stilbenes. The phar­ showed potential for inhibiting antioxidant enzymes leading
macological activities and chemical properties of synthetic to elevated ROS levels and thus resisting the growth of breast
stilbenoids have been increasingly demonstrated. The modifi­ cancer MCF-7 cell line [90]. In 2023, Grau et al. substituted the
cation of PT can be primarily categorized into two aspects: one central double bond with an unsaturated cyclic furan or pyr­
focuses on the carbon-carbon double bond, while the other role, leading to the synthesis of 2-arylbenzofuran-type deriva­
concentrates on the substituent group attached to the ben­ tives or derivatives containing a 2-arylindole nucleus through
zene ring (Figure 3). 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-
7.1. Modification based on carbon-carbon double bonds angiogenic activity while enhancing cytotoxicity against pan­
creatic cancer [22].
González-Sarrías et al. demonstrated that the presence of
a styrene double bond in stilbene was the most crucial deter­
minant for its antiproliferative activity, as evidenced by com­
7.2. Modification based on benzene ring substitutions
parison with corresponding dibenzyl compounds [20]. In 2015,
Madadi et al. synthesized diarylacrylonitrile analogues (1) and 7.2.1. Hydroxyl substitutions
(2) by introducing cyano groups into the double bond of the Constitutive studies conducted by Murias and Wen et al. have
stilbene scaffolds and incorporating methoxy substituents on demonstrated that augmenting the number of ortho positions of
the phenyl ring (Figure 4). Their findings revealed that both hydroxyl (OH) groups on the stilbenol ring enhances both cyto­
compounds (1) and (2) exhibit potential inhibition of acute toxic activity [91] and antioxidant activity [92]. In 2004, Murias
myeloid leukemia cell line MV4–11 growth through interfer­ et al. synthesized a series of methyloxylated and hydroxylated PT
ence with microtubule protein polymerization [89]. In 2020, derivatives and assessed their inhibitory potential against
Pecyna et al. discovered that the presence of a cis- cyclooxygenase-1 (COX-1) and COX-2 enzymes. The results
configuration on the carbon-carbon double bond is indispen­ revealed that hydroxylated PT derivatives exhibited superior
sable for the biological activity of combretastatin A-4 (11), an inhibition toward COX-2, while no significant inhibition was
analogue of PT. They further investigated modifications invol­ observed with methoxylated PT derivatives [93]. In the
ving cyclization and acyclisation on the carbon-carbon double same year, Cheng et al. reported that 3’-hydroxypterostilbene
bond, respectively. It was observed that acyclic modifications, (5) exhibited significant COX-2 inhibition and demonstrated
such as aliphatic amide derivatives, induced dose-dependent stronger anti-colon cancer effects than PT in both in vivo and
apoptosis and cell cycle arrest of A549 cells during the G2/M in vitro studies [19]. In their 2022 study, González-Sarrías et al.
phase. Additionally, piperazine derivatives exhibited tubulin investigated the IC50 values of dietary stilbene, its gut microbial
depolymerization and pro-apoptotic activities. On the other metabolites, and various analogues in human colon cancer cells.
hand, cyclic modifications like aminoimidazole derivatives Their findings revealed that 4-hydroxystilbene (6) exhibited
demonstrated potent cytotoxicity and microtubule higher cytotoxicity compared to PT [20]. In 2023, Florio et al.

Figure 3. Constitutive relationship between PT and its derivatives.

118 X. YU ET AL.

Figure 4. Modifications of PT and its derivatives based on carbon-carbon double bonds.

incorporated various para- or neighboring substituents while developing more potent inhibitors of microtubule protein poly­
preserving the 4’-phenol moiety to synthesize a series of deriva­ merization. Their findings revealed that the biological activity of
tives with partial substitution of the 3,5-dihydroxy group by these drugs is highly dependent on the number and position of
methyl and benzene rings. The derivative (7) exhibited diverse methoxy groups, particularly the 3,4,5-trimethoxy portion on ring
antitumor effects, alongside the identification of antioxidant A which was found to be associated with cytotoxicity and anti­
potential associated with the 4’-OH group [87]. tumor activity [95]. In 2019, Van den Brand et al. conducted
a study on PT and several structurally similar stilbene compounds,
7.2.2. Methoxy substitutions revealing that trans-2,3,’4,5’-trimethoxystilbene (9) exhibited
Although hydroxylated stilbene analogues exhibit significant selective inhibition of the cell cycle in breast tumor cells and
therapeutic potential owing to their diverse biological and phar­ demonstrated enhanced suppression of breast cancer cell migra­
macological activities, their rapid metabolism and limited bioa­ tion [41]. In the same year, Lu et al. conducted a screening of
vailability may impose constraints on their clinical application multiple gefitinib-resi stant NSCLC cell lines using the MTT assay
[94]. Giacomini et al. demonstrated that the introduction of mod­ and discovered that 3,5,4’-trimethoxystilbene (10), a PT deriva­
ifications, such as methoxylation, to polyphenol structures can tive, enhanced the sensitivity of NSCLC cells to gefitinib while
enhance their lipophilicity. This enhancement facilitates cellular inducing apoptosis [79]. In 2022, Huber et al. conducted
uptake, prevents degradation, and improves stability [88]. In a biotransformation reaction on a mixture of resveratrol and PT,
2011, Hasiah et al. investigated the SAR of cytotoxicity and anti­ resulting in the generation of a diverse range of derivatives
oxidant activity in six methoxylated stilbene analogues. They distributed across six distinct scaffolds. The subsequent analysis
discovered that the cytotoxicity and antioxidant activity of of SAR revealed that the presence of methoxy substituents
these compounds were dependent on their structural character­ potentially exerts a favorable impact on the inhibition of Wnt
istics. Notably, (Z)-3,4,4’-trimethoxydiphenylethene (8) exhibited activity. The presence of highly similar structure-determining
a more potent antiproliferative effect than PT in HepG2 cells [63]. clusters, optimally positioned on distinct backbones, was
In 2017, Bukhari et al. conducted a series of derivative synthesis hypothesized in these compounds based on the pharmacophore
and SAR studies on lipid-lowering drugs (11) with the aim of modeling hypothesis developed by the research team [46].
 FUTURE MEDICINAL CHEMISTRY 119

7.2.3. Halogen substitutions cancer cells and exhibit significant pro-apoptotic effects
In 2009, Moran et al. synthesized a series of trans- [88,102]. In 2012, Moser et al. found that benzimidazole ana­
fluorinated analogues based on the diphenylethylene struc­ logues of stilbene exhibited soluble epoxide hydrolase (sEH)
ture, which were subsequently evaluated in lung cancer and inhibition [103]. In the subsequent year, Buscató et al.
melanoma cell lines. One of the difluoro derivatives has designed and synthesized a series of compounds based on
demonstrated potent antiproliferative effects in breast, the (E)-benzimidazole stilbene scaffold. Among these com­
lung, and central nervous system tumors, as well as exhibit­ pounds, the 2-trifluoromethyl substituent (16) exhibited the
ing significant antitumor activity across a range of human lowest IC50 value (~0.6 μM) and effectively inhibited U937 cell
tumor cells, particularly leukemia cells. Additionally, the proliferation [104].
difluoroacetyl derivatives exhibited characteristics of multi­
drug resistance modifiers and demonstrated synergistic
effects against tumor cell proliferation [96].
8. Bioavailability
In 2016, Liu et al. synthesized a series of fluorinated
stilbenes through substitution and Wittig-Horner reactions, Some commonly occurring stilbenes, such as resveratrol, exhi­
followed by an analysis of their tectonic relationships by bit relatively low bioavailability due to their incomplete
comparing the IC50 values with those of two controls, absorption and rapid metabolism within the gastrointestinal
namely resveratrol and tamoxifen. They found that the tract [105]. Owing to the presence of two methoxy groups and
B-ring 4’-site -OCF3-substituted derivatives had a stronger one hydroxyl group, PT demonstrates enhanced lipophilicity
inhibitory effect on the proliferation of MCF-7 cells than the and increased potential for cellular uptake in comparison with
-SCF3-substituted derivatives; the A-ring 4-site-substituted resveratrol, which contains three hydroxyl groups [106].
derivatives had a stronger inhibitory effect on the prolifera­ Additionally, extensive research has demonstrated that PT
tion of MCF-7 cells than the 3,4,5-site-substituted deriva­ exhibits superior bioavailability and bioactivity, along with
tives; and the B-ring inter-substituted derivatives of a prolonged half-life compared to resveratrol under identical
electron-withdrawing groups had a stronger inhibitory experimental conditions [4,107–109]. In terms of pharmacoki­
effect on the proliferation of MCF-7 cells than the para- netics, PT is readily absorbed in the gastrointestinal tract and
substituted derivatives of electron-withdrawing groups. demonstrates extensive distribution to various tissues and
Moreover, 3,5-dimethoxy,3’-trifluoromethoxystilbene (12), organs throughout the body via systemic circulation. The
which has a common A ring with PT, had the strongest ADME study conducted by Prasad et al. revealed that PT
inhibitory effect on the proliferation of MCF-7 cell [97]. exhibits high lipophilicity, low water solubility, and BBB per­
meability, suggesting its potential impact on the systemic and
central nervous system. Furthermore, PT is primarily metabo­
lized by the hepatic cytochrome P450 enzyme system, includ­
7.3. Others
ing various subtypes such as CYP1A2, CYP2C9, and CYP3A4.
The PT-isothiocyanate (13) represents a novel class of The resultant metabolites predominantly comprise glucose-
hybrid compounds, wherein isothiocyanate functionality is aldoxylation products and sulfated derivatives [110–112].
introduced onto the backbone of PT. The compound (13) Currently, the available routes of administration include oral,
exhibited antitumor proliferative and metastatic effects in intravenous, or local administration; however, the sole admin­
breast cancer cell lines MDA-MB-231 and MCF-7, as well as istration of PT often hampers its bioavailability and partially
in mouse models of 4T1 cell-induced metastasis and loaded compromises its anti-cancer efficacy [94,113–115]. In order to
Ehrlich ascites tumors. These effects were potentially enhance the clinical bioavailability of PT, common strategies
mediated through the regulation of the peroxisome prolif­ include the modification of PT prodrugs [116,117], nanoparti­
erator-activated receptor γ activation pathway. Also The cle synthesis [118], and other carriers for transportation, as
compound (13) exhibited superior anti-NF-κB and anti- well as the formation of eutectic mixtures. The incorporation
inflammatory activities compared to PT in lipopolysacchar­ of PT nanoparticles significantly improves water solubility and
ide (LPS)-stimulated RAW264.7 macrophage and keratan drug release, demonstrating exceptional stability under phy­
gum-induced rat paw edema models [98–101]. Moreover, siological conditions. Notably, certain PT nanoparticles
(13) effectively modulated the AR in LNCaP cells expressing demonstrated superior antitumor activity compared to pure
the T877A mutant AR, resulting in apoptosis induction in PT [5,6,32,62]. The drug solubility can be significantly
prostate cancer cells. The suppression of cell proliferation enhanced through the formation of co-crystals, as demon­
and promotion of apoptosis by compound (13) were par­ strated by the examples of piperazine-pterostilbene co-
tially mediated through the inhibition of AR, Akt, and ERK crystals [119] and caffeine co-crystals [120]. Clinical trials are
signaling pathways. The IC50 values for compound (13) currently underway for the oral bioavailability of PT co-crystals
were determined to be 50 ± 50.40 μM and 1 ± 12.45 μM in in comparison to their free form (BIOPTERO) (Bioavailability-
AR-positive (LNCaP) and negative (PC-1) cells, respec­ NCT05561075).
tively [99]. Stilbene structure is one of the most important anticancer
In 2010, Belluti et al. synthesized a series of derivatives (14) pharmacophores. A number of stilbene-based drugs, such as
and (15) that incorporate coumarin into the stilbene frame­ raloxifene, toremifene, or tamoxifen, have already been
work. The aforementioned class of compounds was discovered approved for clinical use [121]. A number of compounds with
to augment the antiproliferative activity of H460 human lung a stilbene structure are also under clinical trial for oncological
120 X. YU ET AL.

applications, such as resveratrol (colorectal cancer- establishing a solid foundation for chemical modification and
NCT00920803, multiple myeloma-NCT00920556, chronic clinical utilization of stilbenes.
obstructive pulmonary disease – NCT03819517); the combretas­
tatin A4 phosphate (advanced Anaplastic Thyroid Cancer-
NCT00060242, advanced Solid Tumors-NCT00003768, 10. Future prospective
NCT00003698); and the vascular disrupting agent OXI-4503
(acute myeloid leukemia and myelodysplastic syndromes – In terms of anti-tumor activity, some excellent PT deriva­
NCT02576301). Exploration of the clinical application of pteros­ tives necessitate further in vivo and clinical testing to ascer­
tilbene began as early as 2016 (amyotrophic lateral sclerosis – tain their efficacy. Reinforcement of the validation process
NCT05095571), with additional clinical trials initiated in 2019 and for these compounds will contribute to bridging the exist­
2020 for acute kidney injury (NCT04342975) and endometrial ing gaps in clinical efficacy or safety, thereby expediting the
cancer (NCT03671811), respectively. Moreover, certain deriva­ advancement of novel drug development. In terms of bioa­
tives have demonstrated enhanced bioavailability compared to vailability, in addition to enhancing the utilization rate of PT
PT, thereby warranting further investigation. Peng et al. discov­ itself, we can also direct our attention toward derivatives
ered that trans-3,5,3‘,4’-tetramethoxystilbene (50.5%) exhibited exhibiting promising clinical potential, thereby achieving
significantly higher oral bioavailability than PT (12.5%) and other the dual optimization of clinical efficacy and cost-
tetramethoxystilbenes [109]. In addition to the formation of effectiveness. Furthermore, PT not only exerts its effects as
eutectic crystals, González-Alfonso et al. discovered that α- a monotherapy in various types of cancer, but also demon­
glucosylation of PT also enhanced its water solubility to approxi­ strates potential as an adjunctive or combination therapy to
mately 0.1 g/L. Furthermore, they demonstrated that PT α-d-glu­ enhance treatment efficacy. The investigation of the syner­
copyranoside exhibited lower toxicity than PT toward human SH- gistic effect of PT holds significant clinical implications. In
S5Y5 neurons, MRC5 fibroblasts, and HT-29 colon carcinoma cells the context of clinically aggressive estrogen receptor-alpha
[122]. In addition, CA-4 (11), a small molecule vascular-targeting (Erα)-negative breast cancers, epigenetic-based interven­
agent that exhibits antivascular activity below the maximum tions such as histone deacetylase (HDAC) inhibitors can be
tolerated dose, demonstrated remarkable growth inhibition employed to modulate ERα expression; however, they often
against the NCI 60 human tumor cell line (with IC50 values entail a multitude of adverse effects. Rishabh et al. demon­
ranging from 0.53 to 2.4 μM) and selectively suppressed neovas­ strated that the combination of PT and resveratrol effec­
cularization in cancerous tissues. Currently, it is undergoing clin­ tively down-regulated SIRT19, a type III histone deacetylase,
ical trials as an anti-tumor vascular disruptor (ovarian cancer- thereby influencing DNA damage and response mechan­
NCT02055690, neuroendocrine tumors- NCT02279602, etc.). isms. This combined therapy induced cell cycle arrest at
However, (11) exhibits poor water solubility and stability, and G2/M and S-phase as well as apoptosis. Additionally, it
the active cis-styrene configuration undergoes isomerization to exhibited enhanced efficacy in augmenting ER-α expression
the corresponding less active trans compound when exposed to while mitigating the adverse effects associated with hor­
heat, light, or hydrophilic media. In order to enhance its thera­ mone-refractory breast cancer [20]. Similar cumulative
peutic potential, phosphorylated prodrugs of (11) have been effects can be observed when combining PT with curcumin
extensively investigated for their anticancer effects in asexual analogues, leading to the activation of lysyl oxidase and
thyroid, non-small cell lung, and ovarian cancers, both as stan­ subsequent inhibition of migration and invasion in hepato­
dalone treatments and in combination with other drugs [88]. cellular carcinoma cells [61]; The combination of PT and
These findings offer valuable insights into strategies aimed at EGCG effectively suppressed the proliferation and induced
improving the bioavailability of PT and its derivatives. apoptosis of pancreatic cancer cell lines MIA PaCa-2 and
By implementing diverse strategies to enhance the bioa­ PANC-1 by modulating distinct points in the mechanistic
vailability of stilbenes, we can significantly amplify the clinical pathway [85]. Moreover, PT holds the potential to augment
significance of these compounds and establish a robust foun­ the efficacy of chemoradiotherapy while mitigating adverse
dation for future clinical trials. effects, rendering it a viable adjunct to conventional ther­
apy. EGFR mutation-positive NSCLC cells typically develop
resistance to Osimertinib monotherapy by activating com­
pensatory pathways in parallel. The combined treatment of
9. Conclusion
PT and Osimertinib exhibited a synergistic effect, overcom­
In our investigation of various cancer treatment methods, we ing this resistance in PC9 cells while also reversing the
observed that PT and its derivatives exhibited potent anti-tumor osimertinib-induced phosphorylation of STAT1, YAP1, and
activity. These compounds often demonstrated similar mechan­ CUB structural domain protein-1 (CDCP1), as well as inhibit­
isms of action, with some derivatives even surpassing the efficacy ing Src phosphorylation [123]. Mannal et al. reported that
of PT itself. To facilitate the development and synthesis of novel the combination of Tamoxifen, a clinically used drug for
pharmaceuticals, we further investigated the underlying struc­ advanced breast and ovarian cancers, with PT exhibits
tural factors responsible for the potent anti-tumor activity exhib­ a cumulative inhibitory effect on breast cancer cells, possi­
ited by these derivatives. Simultaneously, we have bly attributed to its augmentation of apoptosis [31]. These
comprehensively summarized the strategies for enhancing the synergistic effects can enhance the drug sensitivity of tumor
bioavailability of PT and extensively explored the potential appli­ cells and mitigate tolerance or toxicity, thereby creating
cation of its derivatives in terms of bioavailability, thereby favorable conditions for the synthesis of novel therapeutic
 FUTURE MEDICINAL CHEMISTRY 121

agents with potential efficacy in cancer therapy, in conjunc­ 11. Chiou YS, Tsai ML, Nagabhushanam K, et al. Pterostilbene is more
tion with the aforementioned studies and advancements in potent than resveratrol in preventing azoxymethane (aom)-induced
colon tumorigenesis via activation of the NF-E2-related factor 2
administration methods.
(Nrf2)-mediated antioxidant signaling pathway. J Agric Food Chem.
2011 Mar 23;59(6):2725–2733. doi: 10.1021/jf2000103
12. Wawszczyk J, Kapral M, Hollek A, et al. In vitro evaluation of
Funding
antiproliferative and cytotoxic properties of pterostilbene against
The authors acknowledge Shandong Province Chinese medicine science human colon cancer cells. Acta Pol Pharm. 2014 Nov;71
and technology project youth project [Q-2023097]; NATCM’s Project of (6):1051–1055.
High-level Construction of Key TCM Disciplines Marine Traditional Chinese 13. Wawszczyk J, Jesse K, Smolik S, et al. Mechanism of
Medicine; [No. zyyzdxk-2023124]; Shandong University of Traditional pterostilbene-induced cell death in HT-29 colon cancer cells.
Chinese Medicine [2023058, 2023060] for financial support. Molecules. 2022 Jan 7;27(2). doi: 10.3390/molecules27020369
14. Rimando AM, Suh N. Biological/Chemopreventive activity of stil­
benes and their effect on colon cancer. Planta Med. 2008 Oct;74
(13):1635–1643. doi: 10.1055/s-0028-1088301
Disclosure statement 15. Nutakul W, Sobers HS, Qiu P, et al. Inhibitory effects of resveratrol
and pterostilbene on human colon cancer cells: a side-by-side
The authors have no relevant affiliations or financial involvement with comparison. J Agric Food Chem. 2011 Oct 26;59(20):10964–10970.
any organization or entity with a financial interest in or financial conflict doi: 10.1021/jf202846b
with the subject matter or materials discussed in the manuscript. This 16. Paul S, Rimando AM, Lee HJ, et al. Anti-inflammatory action of
includes employment, consultancies, honoraria, stock ownership or pterostilbene is mediated through the p38 mitogen-activated pro­
options, expert testimony, grants or patents received or pending, or tein kinase pathway in colon cancer cells. Cancer Prev Res (Phila).
royalties. 2009 Jul;2(7):650–657. doi: 10.1158/1940-6207.Capr-08-0224
17. Paul S, DeCastro AJ, Lee HJ, et al. Dietary intake of pterostilbene,
a constituent of blueberries, inhibits the beta-catenin/p65 down­
stream signaling pathway and colon carcinogenesis in rats.
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