Polydatin: A natural compound with multifaceted anticancer properties

Abstract

Cancer poses a significant global health challenge, contributing to substantial mortality rates and driving the urgent need for exploration into bioactive compounds with potent anticancer properties. Polydatin (PD), a stilbenoid compound abundant in various fruits and vegetables, has emerged as a promising candidate in cancer research. Renowned in traditional Chinese medicine for its multifaceted biological activities encompassing antioxidant, anti-inflammatory, anticancer, hepatoprotective, neuroprotective, and immunostimulatory effects, PD stands out as a versatile therapeutic agent. This review paper meticulously compiles the diverse anticancer attributes of polydatin across a spectrum of cancer types, elucidating its impact on pivotal cancer hallmarks such as proliferation, migration, metastasis, apoptosis, modulation of the tumour microenvironment, autophagy, and more. Furthermore, the review intricately explores the intricate pathways influenced by polydatin within cancer cells, unveiling its mechanisms of action and identifying potential therapeutic targets. By providing a comprehensive analysis of how polydatin affects various facets of cancer progression and addresses treatment resistance, this paper aims to enhance our understanding of its pivotal role in cancer therapy. Moreover, the synergistic potential of polydatin in combination with other drugs is investigated to underscore its amplified efficacy in combating cancer through innovative mechanism-based strategies. The synthesis of these insights underscores polydatin's significance as a valuable component in the advancement of novel approaches to cancer prevention and treatment.

Goals

This review aims to comprehensively compile and analyze the diverse anticancer attributes of polydatin (PD) across various cancer types, elucidating its impact on pivotal cancer hallmarks such as proliferation, migration, metastasis, apoptosis, and modulation of the tumour microenvironment. Additionally, it explores the intricate pathways influenced by polydatin within cancer cells, unveiling its mechanisms of action and identifying potential therapeutic targets. Moreover, the review investigates polydatin's potential synergistic effects with other anticancer drugs, while also examining its therapeutic and preventive effects against various cancers.

Methods

A systematic review of scientific literature, comprising research articles, clinical trials, and reviews, was conducted to analyze polydatin's anticancer properties. Reputable databases like PubMed, ScienceDirect, and Google Scholar were searched, and selected studies were critically evaluated to extract essential insights into polydatin's mechanisms of action and its interactions with other anticancer drugs, utilizing keywords targeting specific cancer types such as colorectal, oral, breast, and cervical cancer.

Findings

The review and additional online research on polydatin reveal that it exhibits multifaceted biological activities, including antioxidant, anti-inflammatory, and anticancer effects. Across various cancer types, polydatin demonstrates promising properties, impacting key cancer hallmarks such as proliferation and metastasis. These findings underscore polydatin's diverse therapeutic potential, particularly in cancer treatment, by targeting crucial pathways involved in cancer progression and offering insights into its mechanisms of action.

Results

Polydatin shows potential as a valuable component in cancer therapy, addressing various facets of cancer progression and treatment resistance.

Synergistic potential with other drugs suggests amplified efficacy in combating cancer through innovative mechanism-based strategies.

The review underscores the significance of polydatin in the advancement of novel approaches for cancer prevention and treatment.

Graphical abstract

1. Introduction

Cancer, a global health concern, disproportionately affects less developed countries, home to approximately 82 % of the world's population.¹ The rising prevalence of cancer, particularly in low- and middle-income countries (LMICs), is a major threat to sustainable development.² Despite advancements in diagnostic and therapeutic approaches, cancer remains a formidable challenge,¹ exacerbated by increasing urbanization and cancer-associated lifestyle choices like unhealthy dietary patterns.³ While mono-targeted drugs are currently available, targeting a single pathway may result in toxicity and adverse effects. Ineffectiveness, resistance issues, and escalating treatment costs further limit the efficacy of targeted medications. Given the multifactorial nature of cancer, adopting preventative and therapeutic strategies involving drugs targeting multiple biochemical and molecular pathways may be essential to decrease the prevalence and impact of the disease. This approach appears to be the most viable means of addressing the complexity of cancer.⁴ Cancer chemotherapy, a rapidly evolving field in preventive oncology, aims to suppress, completely delay, or even reverse the carcinogenic process using synthetic, pharmacological, or natural substances.^5,6 Employing natural agents for chemoprevention offers several advantages, including safety, efficacy, accessibility, affordability, the potential to overcome resistance to conventional medicines, and the possibility of replacing anticancer pharmaceuticals.⁷ Contrastingly, plants have been utilized since ancient times for extracting valuable bioactive compounds to promote human health and well-being.⁸ Despite the emergence of synthetic therapeutic molecules, natural products remain relevant for disease mitigation and prevention.⁹ Ongoing research employs various approaches to identify phytochemicals from natural sources.¹⁰ Polydatin (PD), a member of the stilbene family, is one such natural compound derived from the roots of Polygonum cuspidatum, a plant indigenous to East Asia. With a history deeply rooted in traditional Chinese medicine, PD has been utilized for its medicinal properties, notably as a painkiller and febrifuge. Its therapeutic potential, particularly in cancer treatment, has attracted significant interest in recent years. PD's chemical structure consists of two phenolic rings connected by a methylene bridge, conferring upon its unique biological activities. Studies have elucidated PD's diverse pharmacological effects, including its antioxidant properties and its ability to modulate various cellular signalling pathways implicated in cancer development and progression11, 12, 13,¹⁰. PD's anticancer activity involves mechanisms such as reactive oxygen species (ROS) control and suppression of the PI3K/AKT pathway.^14,15 Several studies have shown that PI3K/AKT inhibitors enhance the effectiveness of treatments involving 2-deoxy-d-glucose (2-DG) and PD.^16,17 Additionally, PD's positive impact on glucose and lipid management has attracted attention.¹⁸ It enhances 2-DG's anticancer effects by regulating glucose metabolism and blocking the PI3K/AKT pathway, or other pathways. Research investigating PD's impact on various cancer cell lines, including those derived from liver, cervical, and nasopharyngeal tissues, has yielded promising results, suggesting its potential as a broad-spectrum anticancer agent. Given the accessibility and affordability of natural products like PD, its integration into cancer treatment regimens could have significant implications, particularly in LMICs where access to advanced therapies may be limited.¹⁰ This review aims to comprehensively explore PD's anticancer potential, shedding light on its mechanisms of action and its implications for the development of novel therapeutic strategies in the fight against cancer. By elucidating PD's role in cancer prevention and treatment, this research seeks to contribute to the global effort to combat the rising burden of cancer, particularly in resource-constrained settings.

2. Polydatin: structure, chemistry, and biosynthesis

Polydatin (PD), also known as piceid, is a monocrystalline substance and a member of the stilbene family. It is a derivative of the phytoalexin resveratrol (3,4′,5-trihydroxystilbene), where the hydroxyl group at position C-3 is replaced by a glucoside group. The trans-isomers of stilbenes, including PD, are recognized for their higher bioactivity compared to their cis-isomer counterparts.¹⁹ Polydatin's chemical structure and characteristics contribute to its therapeutic effects. There are four derivatives found in nature: cis-resveratrol, cis-polydatin, trans-polydatin, and trans-resveratrol as represented in Fig. 1.^10,20 The biosynthesis of PD involves utilizing the polyketide and phenylpropanoid pathways. The process initiates with phenylalanine ammonia-lyase (PAL), which catalyzes the deamination of phenylalanine to produce cinnamic acid. Cinnamate-4-hydroxylase (C4H) then facilitates the hydroxylation of cinnamic acid, generating p-coumaric acid. Coenzyme A (CoA) ligation occurs through the activity of p-coumaroyl-CoA ligase. Finally, stilbene synthase (STS) combines p-coumaroyl-CoA with three malonyl-CoA molecules to produce resveratrol.²¹ Glucosyltransferases further metabolize resveratrol into other stilbenoids, including polydatin22.

Fig. 1.

Chemical structure and sources of polydatin.

Polydatin is found in various dietary sources, primarily extracted from plants belonging to the Vitaceae, Liliaceae, and Leguminosae families (Fig. 2).²³ The main plant source is Polygonum cuspidatum.²⁴ However, the invasive nature of this plant, particularly in remote mountain regions, can disrupt ecosystems and agricultural potential, posing ecological challenges.²⁵

Fig. 2.

Dietary sources of Polydatin. The concentration of polydatin was measured using chromatographic methods.^{22,41,53,55,56}

Polydatin and resveratrol are both natural compounds with antioxidative properties, but polydatin appears to have a more potent antioxidative effect compared to resveratrol.²⁶ In studies involving rats, polydatin showed a superior effect in increasing the activities of antioxidative enzymes like T-SOD and CAT, as well as the content of GSH, when compared to resveratrol. Additionally, polydatin was found to be the main substance in serum after administration, hinting at its potential as a substitute for resveratrol in clinical antioxidant use.^26,27 On the other hand, resveratrol has been extensively studied for its chemopreventive effects against cardiovascular diseases, ageing, and cancer, although its bioavailability is low due to rapid metabolism.^28,29 In vitro studies have shown that resveratrol has chemopreventive effects, but its cytotoxic action is attributed to its pro-oxidant properties.³⁰ Resveratrol and piceid, a precursor of resveratrol, have been compared in terms of their biological activities.³¹ While resveratrol showed higher inhibition capacity in cell viability than piceid, both compounds exhibited significant cytotoxicity on tumour cells at high concentrations.^32,33 Moreover, polydatin has been investigated for its potential to induce cell cycle arrest and differentiation in human colorectal cancer cells, suggesting its use in combination with chemotherapy for colon cancer.³⁴ Polydatin and DHS (dihydrostilbenes) compounds share several similarities in their antitumor effects, including significant activity against various cancer types such as cervical cancer and lung cancer, as well as the ability to induce cell cycle arrest, thereby impeding cell proliferation and growth.^35,36 However, researchers also demonstrate differences in their mechanisms of action. Polydatin operates through modulation of oxidative stress, inhibition of tumour growth, and induction of apoptosis via pathways like the Akt/GSK-3β/Nrf2/NF-κB signalling cascade.^29,37,38 In contrast, the specific mechanisms underlying the antitumor effects of DHS compounds remain less elucidated, potentially involving distinct pathways related to cell survival and proliferation. Moreover, while Polydatin exhibits efficacy against a broad spectrum of cancers, targeting proteins like p21, p27, CDK2, and Cyclin D1, DHS compounds' precise molecular targets and targeted cancer types are not explicitly specified, necessitating further research for clarification.^36,39 Despite these differences, both Polydatin and DHS compounds demonstrate promising potential as antitumor agents, albeit with variations in their specific mechanisms, targeted cancer types, and molecular pathways involved in their therapeutic effects.^22,40, 41, 42, 43, 44, 45, 46, 47, 48, 49 Studies have demonstrated that polydatin alone or in combination with resveratrol and DHS can modulate cell cycle, differentiation, and apoptosis synergistically, indicating its potential in cancer treatment.^29,31,50,51

Polydatin was originally discovered in grape skin and is primarily sourced from white, red, and grape juices. Cis-PD, another derivative, is predominantly present in rose and effervescent wines. Grapes, berries, peanuts, and pistachios are among the foods containing the most trans-resveratrol, a precursor to polydatin52. Additionally, polydatin is present in various fruits and vegetables, beer, items containing cocoa, and chocolate (Fig. 2).^53,54

The therapeutic and protective effects of polydatin arise from its antioxidant, anti-apoptotic, and anti-inflammatory characteristics.⁵⁷ With more potent antioxidant and anti-inflammatory activity compared to resveratrol, polydatin has been studied for its therapeutic advantages across various pathological conditions, including diabetes, neurodegenerative disorders, rheumatoid diseases, hepatic/respiratory diseases, cardiovascular diseases, skeletal/women disorders, gastrointestinal diseases, and infectious diseases.58, 59, 60, 61, 62, 63, 64, 65, 66 PD's potential in fighting cancer has been confirmed in various studies (Fig. 6), showcasing its efficacy against cervical, nasopharyngeal, and liver cancers. The trans version of PD is well acknowledged in China for its significant therapeutic properties, often used as a fever reducer and painkiller.¹⁰ This makes polydatin a promising candidate for further exploration in cancer treatment and other medical applications.

Fig. 6.

Polydatin (PD) and its mechanisms of action in treating various types of tumours. Polydatin has shown promising results in suppressing the growth of cancer cells, It achieves this by affecting various cellular processes such as cell cycle regulation, apoptosis, DNA damage, ER stress, dysregulation of mitochondria, signalling pathways, and epithelial-to-mesenchymal transition. [↑ = upregulate, ↓ = downregulate, ^┬ = Inhibit, ↑↓ = regulate].

3. Anticancer effect of polydatin on different cancers

3.1. Polydatin in colorectal cancer

Colorectal cancer (CRC) is the third most common type of cancer in the US, and it is the second leading cause of cancer-related mortality. The antitumor effects of polydatin are mediated by diverse cellular and molecular mechanisms. These mechanisms encompass stimulating apoptosis, inhibition, invasion, and proliferation of cancer cells.^67,68 Disruption of mitochondrial function, induction of endoplasmic reticulum stress,⁶⁹ binding more strongly to the target G-quadruplex, and possibly reducing VEGF expression in pancreatic cancer cell lines.^70,71 Ye Jin et al. found that Polydatin at various dosages reduced CRC cell clones and viable cells in Caco-2 and HCT 116 cells. Polydatin treatment also increased apoptosis by upregulating cleaved caspase-3 and-9 and downregulating proliferative indicators such as PCNA (Proliferating cell nuclear antigen).⁷² Moreover in another study, it was also observed that PD causes Caco-2 cells to die by inducing apoptosis, which results in differentiation and cell cycle arrest in human colorectal Caco-2 cells.⁷³

Cancer progression can be inhibited or promoted by the TME (Tumour microenvironment) cytokines. An immunosuppress microenvironment is induced by Th2-associated cytokines including IL-10.⁷⁴ PD considerably lowered this immunosuppressive cytokine in HT-29/MNC cocultures.⁷⁵ Additionally, IL-10 and LPS-stimulated macrophages affect colorectal cancer TME biochemical pathways. Akt, ERK1/2 and EGFR (Epidermal growth factor receptor) are phosphorylated in cancer cells by LPS or IL-10-activated macrophages.⁷⁶ The tumour microenvironment's IL-10 may decrease due to PD. In cancer cells, this may indirectly change EGFR, suppressing Akt and ERK1/2 kinases. RES also directly inhibits EGFR-mediated signalling.⁷⁷ CRC cells are often surrounded by inflammatory cells and intestinal microbiota, especially Escherichia coli which produces lots of LPS. LPS increases tumour extravasation, cell adhesion and intravasation, which may spread colon cancer.⁷⁸ Inflammation is a critical defence mechanism in the colon microenvironment against numerous stimuli, including LPS.⁷⁹ High levels of inflammatory cytokines such as IL-6, IL-8, and TNF-α, can dramatically impact oxidative stress-induced inflammation in the tumour microenvironment (TME). Researchers found that HT-29 cells release inflammatory cytokines such as IL-6, TNF-α and IL-8 after being exposed to LPS stimuli.^80,81 HT-29 cells pre-treated with PD before LPS stimulation show that PD dramatically inhibits IL-8 secretion.⁷⁵ Researchers also examined the expression of Toll-like receptor 4 (TLR-4), a key receptor involved in inflammatory reactions and found no modulation by PD, suggesting PD's involvement in downstream signalling pathways such as NF-ΚB.82, 83, 84

Furthermore, the researchers investigated PD's effects on adhesion molecule expression in HUVECs. They noted a marked increase in adhesion molecule expression induced by the supernatant of LPS-stimulated cancer cells on HUVECs, which was significantly reduced by PD treatment.⁸⁴ This aligns with previous findings on PD's inhibitory effect on E-selectin and VCAM-1 expression on HUVECs treated directly with LPS.^84,85 Additionally, the effect of PD on HUVECs was evaluated independently and results showed a significant reduction in the expression of E-selectin induced by PD, while there was no significant alteration observed in the number of cells positive for ICAM-1 and VCAM-1 expression.^84,86

Researchers have found that polydatin inhibits colon cancer cell proliferation and dispersion. Polydatin also causes mitochondrial dysfunction by reducing MMP (Matrix metalloproteinases) and generating ROS (Reactive oxygen species). It also disrupts calcium homeostasis in the cytosol and mitochondria, causing colon cancer cells to die and inhibiting MAPK and PI3K/AKT protein activation. However, polydatin triggers caspase cascades and proteins involved in ER stress, ER-mitochondria tethering and autophagosome formation in colon cancer.⁸⁷

Modulation of intracellular calcium levels is thought to be a crucial biological activity linked to cell apoptosis, cell cycle and proliferation in many cancers.⁸⁸ Years of research have suggested that cytosolic or mitochondrial calcium increases may trigger apoptosis.⁸⁹ Calcium signalling also affects ROS and MMP formation, which cause apoptosis. For instance, prostate cancer cells produce ROS and activate caspase 3 when calcium levels rise, causing apoptosis.⁹⁰ Mitochondria receive most ER calcium signals. The presence of mitochondria-associated ER membranes (MAMs) may generate calcium influxes. Therefore, MAMs are key structures for apoptosis caused by mitochondria-cytosol calcium homeostasis breakdown.⁹¹ Using 2-APB and BAPTA/AM calcium modulators, Hyocheol Bae et al., studied the two pathways linking polydatin to calcium regulation Fig. 3⁸⁷ BAPTA/AM, a calcium chelator, may bind two calcium ions using four functional carboxylic acid groups, while 2-APB targets IP3Rs to prevent IP3-derived calcium release.92, 93, 94 Hyocheol et al., measured mitochondrial and cytosolic calcium in HCT116 and HT-29 following polydatin therapy. Hyocheol et al. assessed cytosol and mitochondria calcium after polydatin administration in HT-29 and HCT116 cells. The researchers also found increased MAMs and mitochondrial membrane protein expression of VAPB, IP3Rs and VDAC.2-APB or BAPTA/AM also prevented polydatin from raising cytosolic and mitochondrial calcium represented in Fig. 3. The study found that polydatin increased apoptosis in colon cancer cells through calcium regulation, even with these calcium regulators.⁸⁷

Fig. 3.

Mechanism of Polydatin on Colorectal Cancer: Polydatin induces apoptosis in colorectal cancer cells through a multi-step process. Initially, it triggers endoplasmic reticulum (ER) stress, resulting in increased expression of C/EBP homologous protein (CHOP), a key regulator of ER stress-induced apoptosis. This upregulation of CHOP further stimulates apoptotic signalling pathways. Additionally, polydatin disrupts mitochondrial function by reducing mitochondrial membrane potential (MMP), leading to mitochondrial dysfunction and the generation of reactive oxygen species (ROS). Accumulation of ROS increases intracellular calcium levels, intensifying cellular stress. Elevated calcium levels activate caspase 9 and caspase 3, crucial enzymes in the execution phase of apoptosis in colorectal cancer cells.

ER stress disrupts calcium homeostasis, causing cell malfunction and death.^95,96 Prolonged ER stress causes the UPR (unfolded protein response), including three ER proteins: ATF6, IRE1α and PERK (Protein kinase R like endoplasmic reticulum kinase). This response restores protein homeostasis. These proteins are usually inactive and bound to GRP78.⁹⁷ To limit excess protein synthesis in the ER, downstream proteins like eIF2α and GADD153 [C/EBP homologous protein (CHOP)] block mRNA translation.^96,97 Polydatin increases CHOP and ER stress, promoting cancer cell apoptosis.⁶⁹ Increased BAK and BAK protein expression may be linked to Endoplasmic reticulum (ER) Ca^₂₊ mediated death(apoptosis). The temporary overexpression of these proteins releases ER calcium, increasing mitochondrial calcium, and cytochrome c.⁹⁸ Thus polydatin-induced ER stress releases pro-apoptotic proteins, killing cells.⁹⁹

3.2. Polydatin in oral cancer

OSCC (Oral squamous cell carcinoma) a mouth and throat, is the most common type of oral cancer. It's the sixth most common cancer worldwide due to many factors, including modern people's bad diets and smoking.¹⁰⁰ Previous studies have demonstrated that polydatin induces caspase activation in CAL27 and Ca9-22 through the mechanism of cytochrome c release from mitochondria. This, in turn, causes PARP fragmentation, which results in the formation of an apoptotic body, a fragmented nucleus. Therefore, the mitochondrial endogenous route activated by polydatin causes OSCC cell apoptosis.¹⁰¹ One of the main factors affecting OSCC patients' survival adversely is local or distant metastases.¹⁰² The process of epithelial-mesenchymal transition, or EMT, results in intercellular invasion and migration, which can either promote cancer metastasis or healthy embryonic growth.¹⁰³ When E-cadherin is inhibited the gap junctions between the adjacent cells split and acquire mesenchymal cell characteristics leading to EMT in epithelial cells.¹⁰⁴ The overexpression of N-cadherin is a characteristic feature of EMT(epithelial-mesenchymal transition), accompanied by the downregulation of E-cadherin. This process is regulated by a complex interplay of regulated pathways and transcription factors.¹⁰⁵ According to Tae-Hyun Bang et al., polydatin increases the amounts of E-protein cadherin and gene expression, preventing cell invasion and migration. N-cadherin, a marker of mesenchymal cells, was also downregulated after polydatin therapy.¹⁰¹ The regulation of the EMT process is mediated by transcription factors including Slug, Zeb1/2, Twist1/2 and Snail.¹⁰⁶ The upregulation of vimentin and fibronectin expression, along with the downregulation of E-cadherin expression, resulted in the establishment of a full-fledged EMT phenotype.¹⁰⁷ Researchers have found that polydatin therapy reduced the expression of Slug and Snail. Hence, polydatin effectively hinders the movement and infiltration of oral cancer cells by upregulating the expression of E-cadherin and downregulating the expression of N-cadherin through the inhibition of Slug and Snail as represented in Fig. 4.¹⁰¹

Fig. 4.

Mechanism of Polydatin in Oral Cancer: Polydatin treatment effectively inhibits the invasion and migration of oral cancer cells through intricate molecular mechanisms. It achieves this by regulating key adhesion molecules. Specifically, Polydatin upregulates E-cadherin expression, crucial for cell-cell adhesion and metastasis suppression, while downregulating N-cadherin, associated with increased cell motility. These effects are mediated by inhibiting transcription factors Slug and Snail, known regulators of epithelial-mesenchymal transition (EMT). Additionally, Polydatin triggers apoptotic pathways within oral cancer cells by activating caspases through cytochrome C release from mitochondria, leading to PARP fragmentation and apoptotic body formation. These molecular alterations induced by Polydatin administration inhibit oral cancer cell invasion, migration, and survival, offering a potential therapeutic strategy against oral cancer progression.

3.3. Polydatin in Osteosarcoma

Osteosarcomas are tumours that commonly affect children and adolescents, characterized by high proliferation rates of the mesenchymal component that can lead to metastasis and relapse.108, 109, 110, 111 It has been discovered that the therapeutic natural compound polydatin possesses anti-osteoporotic and anti-inflammatory properties. It can also stimulate the Wnt/β-catenin pathway, which in turn stimulates osteogenesis in human bone marrow stromal cells. Studies have shown that polydatin can affect osteosarcoma cell proliferation and induce cell cycle arrest via altering the position of β-catenin. Additionally, polydatin has been shown to have deleterious effects on osteosarcoma cell migration, which may involve EMT mediated by the Wnt/β catenin pathway.¹¹²

According to studies, polydatin increases apoptosis and inhibits the proliferation of osteosarcoma cells by suppressing the β-catenin signalling pathways.¹¹³ According to a paper, polydatin activates ERK1/2 to cause bone marrow stromal cells to migrate.¹¹⁴ ZHAO et al. conducted an experiment in which they examined the cytotoxicity and effectiveness of polydatin on U2OS and MG63 cells. The outcomes showed that polydatin significantly and dose-dependently decreased the viability of U2OS and MG63 cells. Furthermore, it was shown that polydatin significantly reduced the percentage of cells with the ability to migrate. Additionally, the study showed that both U2OS and MG63 cell lines had lower expression of mediators linked to polydatin-induced cell cycle arrest, apoptosis, decreased cell migration and reduced cell proliferation.¹¹⁵ Researchers have also demonstrated that polydatin increased the expression of caspase 3, p21, PARP, and TIMP1 while decreasing the expression of Ki67, cyclin E, cyclin A, MMP2, MMP9, CDK2, and PARP1.¹¹⁵ Pgp is essential for the synthesis of bile, the transport of steroids (i.e., the release of hazardous compounds), and cellular defence and protection in healthy tissues.¹¹⁶ Pgp is increased in osteosarcoma cell lines, and it has been demonstrated that inhibiting its expression is a therapeutic target.¹¹⁷ Polydatin in combination with other compounds increases its efficacy against cancerous cells. It has been shown that the combination of polydatin with paclitaxel-resistant osteosarcoma U2OS and MG63 cell lines by upregulating the expression of caspase 3, p21 and downregulating the expression of cyclin E, CDK2, Ki67 and cyclin A. In U2OS and MG63 cells, paclitaxel and polydatin combined treatment increased PARP1 expression while lowering caspase 3 expression.¹¹⁸ A significant decrease in the number of migrating cells was observed with the combination therapy, and its biological mechanism was linked to increased TIMP1 expression and decreased MMP2 and MMP9 expression.¹¹⁸

The Akt signalling pathway is involved in several physiological and pathological processes in osteosarcoma.¹¹⁸ In osteosarcoma, Akt pathway activation causes apoptosis.¹¹⁹ The researchers found that compared to empty vector-transfected cells, Akt-transfected cells had a significantly lower rate of apoptosis without receiving PD therapy. However, after PD injection, the opposite result was recorded. There was a significant increase in the reduction of apoptotic cells brought on by p-AKT in Akt-transfected cells treated with polydatin. AKT phosphorylation of proteins was also significantly reduced by polydatin therapy in the presence of Akt. This suggests that polydatin inhibited Akt activity to some extent, which in turn caused cell death.¹¹⁵ According to a different study, polydatin in osteosarcoma promotes apoptosis by raising the Bax/Bcl2 ratio and suppresses proliferation by decreasing β-catenin signalling.¹¹⁴

There have been reports that TUG1 (Tumour ultrasound-guided incision) was controlled via the Akt pathway. In osteosarcoma cells, TUG1 was discovered to be increased, and TUG1 knockdown reduced proliferation. After TUG1 was suppressed, Akt phosphorylation was inhibited.¹²⁰ TUG1 increased the invasion, migration, and proliferation of osteosarcomas and upregulated the Akt signalling pathway. Furthermore, Akt activation raised TUG1 expression, resulting in a positive feedback loop.¹¹⁷

3.4. Polydatin in breast cancer

Breast cancer (BC) is the most often diagnosed form of cancer among women and is the leading cause of cancer-related mortality. Breast cancer constitutes 11.7 % of the total cancer cases observed in women, and accounts for 6.9 % of all cancer-related mortalities.¹²¹ Sajia et al. conducted a study to investigate the effects of PD on the human breast cancer cell lines MCF-7 and MDA-MB-231. It was discovered that PD exhibits effective inhibition of cell growth and induces apoptosis by causing cell cycle arrest in the S-phase in various cancer cell lines.¹²² A well-known transcription factor called Creb controls several genes with various biological roles, such as proliferation, survival, memory, and learning.^123,124 Research revealed that Creb is crucial for the growth and spread of several solid cancers. Patients who have a poor prognosis, metastatic disease, and nodal involvement display markedly elevated levels of Creb1 compared to other individuals diagnosed with breast cancer.¹²⁵ For Creb to be activated, Ser133 must either be phosphorylated or the transducer of controlled Creb activity co-activators must be nuclearly translocated.^124,126 In another study, it was discovered that PD significantly and dose-dependently reduced the phosphorylation levels of Creb. Additionally, PD inhibited the activation of Creb by the reduction of Creb phosphorylation, hence limiting the proliferation of breast cancer cells. In recent investigations, it was discovered that Creb regulates around 4000 target genes, including cyclinD1 and cyclin A, which are crucial for cell cycle control.¹²⁷ CyclinD1, functioning as a transcriptional co-regulator, plays a pivotal role in the regulation of cell cycle progression.¹²⁸ To initiate the process of DNA synthesis, it is essential that the levels of CyclinD1 are elevated during the G1 phase. However, for the purpose of facilitating efficient DNA synthesis, it is necessary to subsequently decrease the levels of CyclinD1 to a low state during the S phase. The reactivation of CyclinD1 is necessary during the G2 phase to maintain cellular proliferation.¹²⁹ When breast cancer cells received PD therapy for 2 h, it was discovered that Creb's phosphorylation levels started to decline, whereas cyclin D1's expression levels started to decline after 8 h of treatment. Hence, a hypothesis was formulated suggesting that the inhibitory impact of PD might be linked to the suppression of Creb phosphorylation. This, in turn, would lead to the inhibition of cyclinD1 transcription, halting cell cycle progression at the S phase. Ultimately, this cascade of events would result in the apoptosis-mediated death of breast cancer cells.¹²² Multiple studies have demonstrated a correlation between cyclinD1 and β-catenin in the development of breast cancer, with findings indicating an increase in β-catenin and cyclin D1 levels in breast cancer cases.¹³⁰ The protein β-Catenin plays a multifaceted role and is particularly important as a primary mediator of Wnt signalling. The upregulation of Wnts leads to the translocation of β-catenin into the nucleus, thereby influencing the expression of many genes. One of the genes linked to the proliferative and oncogenic properties of β-catenin is cyclin D1.^131,132 The downregulation of cyclin D1 and MMP9 expression occurs as a result of the inactivation of Wnt/β-catenin signalling, which is directly associated with the progression of cancer.^133,134 Recent investigations have indicated that Wnt activation exerts an influence on both basal-like and TNBC (triple-negative breast cancers). Additionally, Schade et al., discovered that ERBB2–mediated breast breast-cancer depends heavily on β-catenin signalling.¹³⁵

Researchers found that PD-AuNP and Dox-AuNP therapy dramatically decreased cyclin D1 and β-catenin expression. Research suggests that IL6 is essential for triple-negative breast cancer growth.^136,137 IL-6 signalling between breast cancer cells and LECs increases cancer cell proliferation and viability. Additionally, IL6 enhances breast cancer cell migration. In tumour-connected or distant organ lymphatic vessels, IL-6 binds to the receptor. IL-6 triggers STAT3, which boosts LEC CCL5 production and release. CCL5 enhances lung, thoracic, and lymph node metastasis.¹³⁸ Researchers discovered that PD therapy markedly reduced the levels of IL-6 in tumour tissue homogenate.¹³⁹ Min Liu et al., discovered that in a mouse model, PD has the potential to decrease distant metastasis and inhibit the activation of STAT3 and JAK2 phosphorylation, which are responsible for the production of proteins that promote pyroptosis, such as IL-18, NLRP3, IL-1β and Caspase 1 and 3. PD has also been shown to promote pyroptosis and limit tumour growth via the JAK2/STAT3 pathway.¹⁴⁰ Pyroptosis affects tumour growth, prognosis, and immunotherapy.¹⁴¹ It was discovered that PD increased caspase-3 activity and decreased JAK2 and STAT3 phosphorylation, which increased apoptosis in TNBC. In TNBC, the formation of plasma membrane holes resulted in cell death and the release of inflammatory mediators. According to the researchers' findings, when a high-fat diet is consumed, apoptosis and pyroptosis are critical processes in the development of TNBC.¹⁴⁰

3.5. Polydatin in blood cancer

Leukaemia is the most commonly occurring form of malignancy and represents the primary cause of mortality associated with cancer in those who are under the age of 20.¹⁴² Researchers conducted a study in which they investigated the effects of PD on cell proliferation in MOLT-4 leukaemia cell lines. Their findings revealed that PD induced mitochondria-mediated apoptosis and cell cycle arrest. Additionally, they observed that these effects were enhanced by the presence of a JAK2 inhibitor. Also, it has been demonstrated that PD triggers apoptosis in human leukaemia cells through the intrinsic mitochondria-mediated pathway, thereby establishing its potential as a viable therapeutic approach for leukaemia treatment.¹⁴³ Many intracellular signalling pathways use reactive oxygen species (ROS) as a mediator. However, an excessive production of ROS can lead to the disruption of the mitochondrial membrane potential, ultimately inducing cell death.¹⁴⁴ Researchers have also shown that PD therapy significantly increased ROS production concurrently with mitochondrial-mediated leukaemia-cell apoptosis, indicating that apoptosis was probably induced via ROS production.¹⁴³

Numerous kinds of cancer, including haematological malignancies, have been associated with constant activation of STAT family members, while the transcriptional activation of STAT proteins often requires JAK-mediated tyrosine phosphorylation.¹⁴⁵ A particular somatic gain of function mutation in JAK2 (JAK2 V617F) is present in over 90 % of individuals diagnosed with polycythaemia vera, and around 50 % of those with primary myelofibrosis and as well as thrombocythemia.^146,147 There has been a proposal suggesting the potential utilisation of JAK2 inhibitors and inhibitors of downstream effectors such as Bcl-2/Bcl extra-large (ABT-737), to enhance the efficacy of polycythaemia vera treatment.¹⁴⁸ Treatment for all subtypes characterized by abnormal JAK/STAT signalling is thought to be successful with this approach. The results of the study revealed that the utilisation of a JAK2 inhibitor effectively increased the inhibitory effects on the cell cycle and induction of apoptosis, as demonstrated by PD.¹⁴³

According to Wang et al., PD may efficiently induce apoptosis in THP-1 cells through the downregulation of Bcl-2 expression and the upregulation of the Bax expression., suggesting that the development of PD may be an option for treating acute monocytic leukaemia. Additionally, it was discovered that the administration of PD to THP-1 cells resulted in an increase in the expression of cyclin A and the number of cells in the S phase, while the expression of cyclin D1 and the number of cells in the G0/G1 phase decreased. This finding indicates that the presence of PD has the potential to inhibit the proliferation of THP-1 cells through the modulation of cyclin D1 and cyclin A expression, resulting in cell cycle arrest specifically at the S phase. Therefore, the findings of their research indicate that PD exhibits a significant ability to inhibit the proliferation of THP-1 cells and induce their apoptosis by regulating the expression of cyclin D1, cyclin A, Bax and Bcl-2 in a dose-dependent manner. These results suggest that PD has the potential to be a promising therapeutic option for the control of acute monocytic leukaemia.¹⁴⁹

3.6. Polydatin in skin cancer

In vitro studies have shown that polydatin has an impact on keratinocytes' EGFR pathway, as well as how it works to reduce inflammation and support skin regeneration function.^150,151 The resistant ability of keratinocytes to oxidative stress and heat shock is modulated by the stimulation of adaptive inflammatory/stress responses through the cytoplasmic route of the epidermal growth factor receptor (EGFR).¹⁵⁰ The main antioxidant or free radical scavenging properties of polydatin are linked with its health advantages. Polydatin has been seen to regulate the expression of the IL-8 gene. It is worth noting that interleukin-8 (IL-8) has an important function in the development of cutaneous adverse events associated with anti-EGFR therapy. This further supports the potential therapeutic application of polydatin in the treatment of skin disorders.^40,152 Ravagnan et al. conducted a study whereby they found that resveratrol and polydatin possess the ability to regulate the production of IL-8, IL-6, and TNF-α genes in human keratinocytes (HaCaT) subjected to heat stress. The expression of these genes was seen to be reduced in HaCaT cells following a 24-h pretreatment with polydatin and resveratrol. Both drugs elevated the expression of heat shock protein 70B' (Hsp70B'), leading to enhanced skin regeneration and reduced cellular damage.¹⁵³ In their study, Fuggetta et al. investigated the effects of a topical moisturiser containing polydatin on the prevention of skin rash in a group of 34 patients diagnosed with mutant non-small cell lung cancer (NSCLC) who were undergoing therapy with the EGFR-TKi afatinib. The findings of the study indicate that the application of a cream containing polydatin can effectively reduce the occurrence of moderate to severe skin toxicities, while not introducing any additional adverse effects.¹⁵⁴ Researchers have noted that individuals receiving a greater dose of polydatin-based products experienced a rapid improvement in their papulopustular rash on the skin (PH151). The typical cutaneous side effects associated with antineoplastic EGFRi treatments, which oncologic patients must inevitably experience, were quickly and safely reduced, or controlled by polydatin cream.¹⁵⁵

3.7. Polydatin in ovarian cancer

Ovarian cancer is a deadly illness with a poor prognosis for women who have the disease in an advanced stage.¹⁶⁶ Advanced ovarian cancer is often associated with ascites, which is defined as an excessive accumulation of bodily fluid in the abdominal cavity.^167,168 Ascites result from vascular endothelial growth factor (VEGF) overexpression, which restricts the permeability of lymphatic and blood arteries at the peritoneal wall. Ascitic fluid, which can readily move throughout the abdominal cavity, contains malignant ovarian cells. The floating cancer cells often form minute 3D aggregates throughout their circulation in the abdominal cavity, which may help them survive.¹⁶⁸ Therefore, these three-dimensional cell aggregates could be a source of cancer cells that eventually grow into microscopic tumours that spread uncontrollably. It has been demonstrated that polydatin, acetyl-resveratrol, and resveratrol can prevent ovarian cancer cell lines SKOV-3 and OVCAR-8 from forming 3D cell aggregates. Apoptosis and changes to certain signalling proteins are thought to be the root causes of growth inhibition. These chemicals had different effects depending on the cell line. In the SKOV-3 cell line, EGFR and Her-2 activation are influenced by resveratrol and polydatin, but not by acetyl-resveratrol. Furthermore, VEGF secretion in the SKOV-3 cell clusters is seen to decrease in a dose-dependent manner. Polydatin and resveratrol regulated Erk's activation in the OVCAR-8 cell line. Using 3D cell aggregates, Simon J. Hogg et al. evaluated the antigrowth efficacy of resveratrol and its derivatives against the SKOV-3 and OVCAR-8 cell lines. The SKOV-3 cell line exhibits significant expression of the tyrosine kinase receptors EGFR and Her-2, which have been proposed as putative targets of resveratrol. Both cell lines show distinct genetic and molecular properties, even though the OVCAR-8 cell line expresses these receptors less than the other.¹⁶⁹

It was discovered that PD inhibited the growth of ovarian cancer cell lines SKOV-8 and OVCAR-3 by lowering EGFR phosphorylation levels. This increased the chances of the cells committing suicide. PD restricts the growth, migration, and invasion of ovarian cancer cells by inhibiting the expression of the PI3K protein, which is the mainstay of treatment for the disease. By reducing EGFR phosphorylation and the generation of ERK and VEGF, PD stopped the 3-D cell aggregation of ovarian cancer cell lines.¹⁷⁰ Polydatin has been shown in previous studies to decrease PI3K protein expression and to stop, A2780, OVCAR-3 and HO-8910 cells from growing, migrating, and invading. PI3K is the target of PD since increasing PI3K protein expression considerably reduces the inhibitory effect of PD on the migration, invasion, and proliferation of the A2780, OVCAR-3 and HO8910 cell lines as represented in Fig. 6 and Table 1. Experimental evidence suggests that PD may be used to treat ovarian cancers since it can prevent these cell lines from growing, migrating, and invading by downregulating the expression of the PI3K protein165. It has been discovered that polydatin inhibits the production of inflammatory molecules in ulcerative colitis-affected animals via deactivating the NF-kB pathway.¹⁷¹ Polydatin's potential anticancer and antimetastatic properties in Lewis lung cancer xenografts may stem from its inhibition of endothelial cell angiogenesis.¹⁷² PD protects ovarian cancer cells from inflammatory damage by promoting apoptosis via the phosphoinositide 3-kinase//mammalian target of the rapamycin (mTOR) protein kinase pathway.^172,173 (see Table 2 and Fig. 7)

Table 1.

Effects of polydatin against different cancers.

Cancer type	Cell line	Study type	Results	References
Colorectal cancer	Caco2, HCT-116	In vivo (Mice), in vitro	↑ cleaved caspase-3 and 9 expression, inhibit proliferation	72
	CT26, HCT116	In vitro and in vivo(Mice)	Inhibit proliferation, ↑ BMP signalling and ↑ radiosensitivity	156
Lung cancer	A549, NCI–H1975,	In vitro	Upregulates Bax and downregulates Bcl-2 to induce apoptosis and S-phase cell cycle arrest.	157
			↑ Bax, ↓ Bcl-2 and cyclin D1 expression, regulating mTOR pathway.	158
	NSCLC cell line (A549, H1299)	In vitro	NLRP3 inflammasome inhibition, NSCLC cell proliferation, migration, and phosphor–NF–κB p6 expression decrease, NF-κB pathway activation.	67
Osteosarcoma	U–2OS, MG‐63,143B	In vitro	↑expression of p21, PARP, caspase 3, and TIMP-1. Reduced expression of cyclins A and E, Ki67 CDK2, MMP-2 and 9, PARP1.	115
	(hFOB1.19)		↑ Bax expression, ↓ the proliferation of cells, Caspase 3, Bcl-2 expression and inhibit β-catenin signalling	113
	(Saos-2/Dox, MG-63/Dox)		↑ PIC3K3, Atg14, Atg12, and BECN, expression, Inhibit TUG1/Akt and STAT3 signalling pathway activity	159
Blood cancer	THP-1, MOLT-4	In vitro	increased Bax and cyclin A expression, stopping S phase cells, decreased cyclin D1 and Bc1–2 expression, inhibiting growth.	149 143
Liver cancer	HL-7702, HCC, HepG2, SMMC-7721, HCCLM3, LO2	In vitro and in vivo (Mice)	↑ caspase 9 and 3 activity, TUNEL activity Bax expression,	160,161
			↓ expression of Ki-67 and Bcl-2, inhibit Wnt/β-catenin, Akt/STAT3 signalling pathway.
Breast cancer	MCF-7, MDA-MB-231	In vitro	Inhibit G6PD activity, ↑autophagosomes formation, ↓ cyclin D1 expression, CREB level, ↑ cell cycle arrest in S phase	58,122
	4T1, MCF-7	In vitro, in vivo(Mice)	Inhibits PI3K/Akt/ROS/HIF-1α signalling	162
Cervical cancer	HeLa cells,	In vitro	Inhibit mTOR/Akt/PI3K signalling pathway.	163
	CaSki, C33A	In vivo (Mice), in vitro	Inhibit migration, proliferation and c-Myc, regulate cyclin E1, cyclin D1, p27, p271, CDK4, CDK2, EMT markers	160
Oral cancer	Ca9-22, CAl27	In vitro	↑ N-cadherin	101
			↓ E-cadherin
			↑↓ Snail, Slug, Zeb1/2, Twist1/2
Skin cancer	HaCaT, NSCLC	In vitro	↑↓ EGFR, IL-6,IL-8,TNF-α, reduce inflammation	150,151,164
Ovarian cancer	OVCAR-3, OVCAR-8, A2780, and HO8910	In vitro	Inhibit proliferation, migration, and invasiveness, ↓ PI3K protein	165

Table 2.

Summary of Polydatin in combination with other drugs in different cancers.

Cancer type	Polydatin in combination	Molecular targets of activation and inhibition	References
Colorectal	PD + 5-FU	↑ apoptotic signals such as BAK, BAX, cleaved caspase-3 and 9, Cytochrome C. ↑ responsiveness to chemotherapy.	87,267,268
	PD + radiotherapy	Slows cancer growth and promotes apoptosis.	156
Oral	PD + PLGA-NPs	↓ the frequency and size of tumours.	272
Osteosarcoma	PD + doxorubicin	Anti-proliferative and apoptosis-inducing properties enhanced.	273
Breast	PD + 2-DG	Prevents glycolysis and induces apoptosis, ↓ proliferation and migration.	162
	PD ₊ BRU	Inhibits the Nrf2/HO-1 and NQO1 pathways, induces the generation of reactive oxygen species (ROS), and inhibits TNBC cell proliferation.	284,285,287,293

Fig. 7.

Effect of Polydatin on Cervical Cancer: The impact of Polydatin on Cervical Cancer involves a targeted approach towards inhibiting the c-Myc signalling pathway. By doing so, Polydatin enhances the production of E-cadherin, a pivotal protein that supports cell-cell adhesion and suppresses metastasis. Simultaneously, Polydatin reduces the levels of N-cadherin, a molecule linked to increased cell motility and invasiveness, effectively impeding cell metastasis. Additionally, Polydatin downregulates the transcription of p21, a key player in cell cycle regulation, while promoting the degradation of p27, another regulator of the cell cycle. This dual mechanism results in G1 phase cell cycle arrest, halting cell proliferation and contributing significantly to the suppression of tumour growth and progression in cervical cancer. [↑ = upregulate,↓ = downregulate, ^┬ = Inhibit, ↑↓ = regulate].

3.8. Polydatin in cervical cancer

According to incidence and fatality rates among females, cervical cancer ranks fourth among all malignancies.¹²¹ The majority of developing countries have high rates of cervical cancer-related mortality among females, with these regions having the highest rates of cervical cancer incidence.^174,175 The high prevalence of human papillomavirus (HPV) infection is directly associated with cervical cancer.¹⁷⁶ Furthermore, the development and course of cervical cancer are associated with a variety of metabolic alterations in addition to epigenetic and genetic changes.^177,178 A unique therapy approach known as stilbenes has proven to be a successful and promising choice for treating many different types of cancer.179, 180, 181, 182 It has been demonstrated that stilbene PD reduces the ability of NSCLC cells to metastasize and inhibits colorectal cancer cell proliferation.^68,72 Scientists have discovered that PD prevents cervical cancer cells from proliferating, progressing through the cell cycle, and migrating or invading other cells by controlling the c-Myc pathway.¹⁶⁰ The proto-oncogene c-Myc in human cells is considered to be the homolog of v-Myc. Multiple studies have shown that c-Myc functions as a highly effective transcription factor.¹⁸³ The regulation of c-Myc expression is well controlled during regular cell proliferation, however, an increase in c-Myc expression is commonly observed in malignancies originating from several histogenetic sources. The findings underscore the potential significance of c-Myc as a diagnostic marker in cervical cancer.184, 185, 186 This is supported by evidence indicating a positive correlation between the expression of c-Myc and the severity of histological diagnosis in cervical cancer.187, 188, 189 The study conducted by researchers revealed that following PD therapy, there was a notable decrease in the expression of the proto-oncogene c-Myc in two human cervical cancer cell lines (C33A and Caski). This reduction occurred in a manner that was dependent on the dosage and duration of the therapy and was observed at both the protein and mRNA levels.¹⁶⁰ Furthermore, by means of transcriptional control and post-transcriptional modification pathways, c-Myc has the ability to exert an impact on the expression of a multitude of proteins that are associated with the cell cycle and metastasis.189, 190, 191, 192, 193

By using MTT assays and similar experiments, researchers have demonstrated that the partial restoration of cell growth and proliferation, which is hindered by PD, may be achieved by overexpressing c-Myc. This restoration is evidenced by the recovery of the cell cycle and the synthesis of proteins associated with the cell cycle. Multiple results have indicated that c-Myc possesses the ability to regulate many proteins associated with the cell cycle, hence exerting control over the advancement of the cell cycle during cellular proliferation.¹⁹⁴ The cell cycle is regulated by c-Myc through the inhibition of p21 transcription and the promotion of p27 degradation.¹⁹⁵ A number of studies have reported that the tumour suppressor gene p21 commonly induces cell cycle arrest in the G1 phase.^194,196,197 The regulatory influence of the proto-oncogene c-Myc on the cell cycle can be reduced by inhibiting the promoter of p21.¹⁹⁵ Moreover, the tumour suppressor gene p27 can prevent cells from moving from the G1 to the S phase.^194,198 Recent research has demonstrated that the transcriptional promoter of p27 can be inhibited by c-Myc and that this promotes p27 degradation through post-transcriptional regulation.¹⁹⁵

Cyclin D1 binds to CDK4 to produce a complex that helps in cell proliferation during the cell cycle. However, it has been observed that p21 can form a complex with CDK4, thereby inhibiting its interaction with Cyclin D1. Consequently, this interaction effectively halts the progression of the cell cycle specifically in the G1/S phase.¹⁹⁹ To regulate the progression of the cell cycle, p21 can inhibit many cell cycle complexes, including CDK2/Cyclin E1.¹⁹⁷ Normally, Cyclin E forms a complex with CDK2 to aid in cell cycle advancement. The main target of p27 is CDK2. Through its kinase binding domain, p27 has the ability to hinder CDK2, hence blocking the interaction of the CDK2/Cyclin E1 complex and inhibiting development of the cell cycle.^198,200 Researchers hypothesise that the inhibition of the c-Myc signalling pathway, which therefore hinders the production of CDK and cyclin proteins, leading to a reduction in cell proliferation activity, may potentially result in the upregulation of p27 and p21 proteins in cells. Moreover, previous studies have provided evidence that the c-Myc protein possesses the ability to induce the transcriptional synthesis of various cyclin and CDK proteins.^195,201 As a result, c-Myc inhibition caused by PD could possibly be directly responsible for the inhibition of CDK and cyclin proteins. Furthermore, it has been observed in experiments involving cell migration and invasion that the overexpression of c-Myc can partially counteract the inhibitory effects of PD on proteins associated with cell invasion, migration, and epithelial-mesenchymal transition (EMT). The transcription factor known as Snail and Slug plays a critical role in the process of epithelial-mesenchymal transition (EMT) by facilitating the upregulation of N-cadherin expression while simultaneously repressing the expression of E-cadherin.202, 203, 204, 205 The observed correlation between changes in Snail and Slug levels and c-Myc can potentially be elucidated by the discovery that c-Myc can enhance the transcriptional activity of the Slug and Snail genes.206, 207, 208, 209 Moreover, the Snail and Slug may be responsible for alterations in N-cadherin and E-cadherin expression. It has been suggested by researchers that Polydatin may inhibit the activity of the c-Myc signalling pathway, thereby increasing the synthesis of E-cadherin, decreasing the expression of N-cadherin, and ultimately inhibiting the ability of cells to spread.¹⁶⁰

3.9. Polydatin in lung cancer

Lung cancer ranks as the second most common form of cancer among both males and females on a global scale, and it is associated with the greatest mortality rate among all cancer-related deaths.²¹⁰ The research of phytochemicals as prospective therapeutics for this specific cancer type has been facilitated by recent advancements in the field of phytochemistry.²¹¹ Researchers have conducted investigations on the A549 lung cancer cell line to explore the anticancer characteristics and mode of action of polydatin. According to research findings, it has been indicated that polydatin exhibits the ability to prevent the proliferation of A549 cells by inducing DNA damage and halting their cell cycle progression (Fig. 8).¹⁵⁸ Furthermore, it has been discovered that polydatin causes these cells to undergo apoptosis, increased cell cycle arrest, and decreased DNA synthesis, all of which result in cell death.^73,113,172

Fig. 8.

Mechanism of polydatin-induced senescence in lung cancer (A549) cells. The mechanism of polydatin-induced senescence in lung cancer (A549) cells involves the initiation of DNA damage by polydatin, leading to the activation of the DNA damage response (DDR) pathway mediated by ATM, ATR, and DNA-PKc. The regulation of the cell cycle inhibitor p21 is intricately linked to the level of DNA damage, primarily controlled by the tumour suppressor protein p53. Additionally, the maintenance of p21 expression is modulated by the protein 4EBP1 through the mTOR pathway. The activation of p21 can drive either cellular senescence or apoptosis, determined by specific cleavage events orchestrated by caspases. Furthermore, the cellular localization of p21 is pivotal in dictating cell fate; cytoplasmic localization inhibits cell death pathways, while nuclear localization promotes apoptosis and triggers cell cycle arrest.

According to research, polydatin induces an apoptotic S-phase cell cycle arrest, which can stop cells from growing.¹⁵⁷ Additionally, pterostilbene can impede telomerase activity, cause DNA damage, activate p53 and p21, lead to an extended S-phase arrest, and ultimately bring about senescence.^212,213 By encouraging the activation of p53 and p21 proteins, several factors, including oxidative stress, telomere shortening, oncogene activation and DNA damage can cause senescence.^214,215 The level of stress experienced by cancer cells plays a crucial role in determining whether they undergo apoptosis or senescence. Senescence-related anti-proliferative reactions can be triggered by lower levels of DNA damage without triggering the cascades of caspase activity that would otherwise cause apoptosis.²¹⁶ Polydatin-induced senescent cells showed no change in caspase expression, but the levels of procaspases 3 and 9 were dramatically lowered in cells treated with higher concentrations which causes cell death by apoptosis.¹⁵⁸ It has been discovered that several chemotherapy medications, such as docetaxel, 5-azacytidine, and doxorubicin, cause cellular senescence at low concentrations while causing apoptosis at greater ones.²¹⁷

The fate of cells is significantly impacted by p53 and p21 DNA damage response proteins. The amounts of the proteins p21 and p53 increased in response to DNA damage caused by polydatin. Senescent cells had significantly higher levels of p21 than untreated ones. In contrast to senescent cells, the amount of p53 was still high but the level of p21 was significantly decreased at greater doses of polydatin that caused apoptosis (Fig. 8). P53 was more highly expressed in human diploid fibroblast cells (IMR-90), p21 expression decreased, and the solubility of the Bax protein was increased.²¹⁸ According to reports, the Myc protein specifically binds to the p21 promoter to suppress p53-mediated p21 transcription, which causes p21 to be downregulated in apoptotic cells.²¹⁹ Furthermore, it is speculated that if caspase-3 breaks down p21, the DNA damage response would be pushed towards apoptosis.²²⁰ The location of p21 is also crucial in determining cell fate. By binding to procaspase-3, SAP, and ASK1 kinases and decreasing their catalytic activity, p21's cytoplasmic localization prevents apoptosis and cell death. In contrast, p21's nuclear localization causes cell cycle arrest and death.²²¹

Research has demonstrated that p21 is present in the cytoplasm of untreated cells. On the other hand, p21 was found in the cytoplasm and nucleus of senescent cells and the nucleus of apoptotic cells after polydatin treatment. Because of its cytosolic distribution, p21's co-localization in the nucleus and cytoplasm may suggest that the cells have suffered cell cycle arrest and are metabolically active. Additionally, p21 stability is positively regulated by mTORC1 activation and 4E-BP1 phosphorylation.²²² According to reports, in response to DNA damage, mTORC1 stabilises and activates p53 via the p38/mTORC1/MAPK-Akt/S6K1 pathway. In lower concentrations of polydatin, where senescence was observed, p21 expression was higher, and mTOR pathway proteins, including mTOR, P70S6K, and 4EBP1, were constitutively activated (Fig. 8).²²³ However, in higher concentrations that resulted in apoptosis, there was a significant decrease in the proteins that activate the mTOR pathway. Therefore, polydatin may cause senescence by stimulating the proteins involved in the p21, p53, and mTOR pathways. The outcome of treatment with polydatin depends on the degree of damaged DNA. Induction of senescence in tumour cells following medication therapy could have potential implications for tumour progression, as the production of, oxidative stress, reduction of cell proliferation and DNA damage are essential processes anti-cancerous agents.^224,225 Senescence is regulated by several pathways, one of which is the mTOR pathway.²²⁶ Activation of the AKT/PI3K/mTOR network has been connected to the production of pro-inflammatory cytokines, including G-CSF, TNF-α, IL-8, and IL-6.^227,228

Researchers found that polydatin suppressed the NF-kB pathway, which in turn prevented the development and metastasis of NSCLC cells via inhibiting the NLRP3 inflammasome. Thus, polydatin might be a helpful medication for the management of NSCLC. Polydatin caused a dose-dependent reduction of cell proliferation in both A549 and H1299 cells. In addition, polydatin was found to stop NSCLC cells from migrating. Therefore, polydatin could be used as a potent anti-cancer medication to treat NSCLC.⁶⁷ It was found that Polydatin could control the MAPK, PI3K/AKT, NF-kB, and Nrf2/HO-1 pathways to decrease mast cell-mediated allergic inflammation.³⁸ Furthermore, it was shown that polydatin decreased renal inflammation by preventing the NF-kB/NLRP3 inflammasome from being activated.²²⁹ The formation of an active inflammasome was achieved through the assembly of NLRP3, ASC, and pro-caspase 1, which collectively contribute to its functional properties. The activation of the NLRP3 inflammasome leads to the cleavage of pro-IL-1 and pro-IL-18 by caspase-1, resulting in the generation of their mature and bioactive forms. Additionally, this activation triggers the proteolytic processing of pro caspase-1 into its active form.²³⁰ It has been shown that the inflammatory signalling system controlled by ASC contributes to tumorigenesis.²³¹ In a study conducted by researchers, it was observed that the administration of polydatin resulted in a reduction in the relative expression of ASC, NLRP3, caspase-1, and pro-caspase-1 in non-small cell lung cancer (NSCLC) cells. This finding suggests that polydatin has a dose-dependent inhibitory effect on the activation of the NLRP3 inflammasome in NSCLC. Therefore, it was determined by researchers that polydatin effectively inhibited the proliferation and metastasis of non-small cell lung cancer (NSCLC) cells through the inhibition of NLRP3 inflammasome activation.⁶⁷

Cell proliferation, Inflammation, survival, and immunity are only a few of the critical activities in life that are influenced by the widely present transcription factor family known as NF-kB.^232,233 Inactivation of the NF-kB complex, which consists of the p50 and p65 subunits as a dimer that remains in the cytoplasm, is brought about by binding to the NF-kB inhibitor.²³⁴ The regulation of pro-inflammatory cytokine production occurs following the phosphorylation of the p65 subunit, which subsequently enhances the transcriptional activity of NF-kB.²³⁵ Inflammatory cytokine production is mostly regulated by NF-kB, and the inflammasome NLRP3 is activated by this protein.²³⁶. The process of the inflammatory response involves various essential stages, such as the initiation of the transcription factor NF-kB and the cleavage of IL-1β by caspase-1.²³⁷ Previous research has provided evidence that the upregulation of NLRP3 in response to NF-kB is capable of inducing the activation of the NLRP3 inflammasome in the presence of ATP, thereby establishing a positive association between these two molecules.²³⁸ The latest research findings indicate that polydatin effectively inhibited the NF-kB pathway in non-small cell lung cancer (NSCLC) cells by suppressing the production of phosphorylated NF-kB p65. The study found that the inhibitory impact of polydatin on the proliferation and migration of non-small cell lung cancer (NSCLC) cells was nullified upon activation of the NF-kB pathway by TNF-α. This suggests that polydatin hinders the proliferation and migration of NSCLC cells by inhibiting the NF-kB pathway. The upregulation of NLRP3 expression in response to TNF-α indicates the modulation of the NF-kB pathway.⁶⁷

3.10. Polydatin in hepatocellular carcinoma

The research investigation demonstrated that polydatin exhibits a significant dose-dependent inhibition of HCCLM3 cell invasion and migration.¹⁶¹ Prior studies have demonstrated that EMT (epithelial-mesenchymal transition) has the potential to enhance cellular invasion and migration in several cancer types.^239,240 The study conducted an observation on the effects of polydatin treatment on HCCLM3 cells. The results revealed that polydatin treatment resulted in an upregulation of E-cadherin expression levels and a downregulation of N-cadherin and vimentin expression levels. These findings suggest that polydatin induces epithelial-mesenchymal transition (EMT) in HCCLM3 cells, hence inhibiting their migratory and invasion capabilities.¹⁶¹ Multiple studies have indicated that the PI3K/AKT, JAK1/STAT3, and p38 signalling pathways play significant roles in the progression of hepatocellular carcinoma (HCC) and are closely associated with epithelial-mesenchymal transition (EMT) in the spread of cancer.²⁴¹ Disruption of tumour cell polarity, morphological changes in tumour cells and the loss of tumour cell-cell junctions are caused by the activation of AKT, which in turn promotes tumour cell motility.^242,243 AKT activation also prevents E-cadherin transcription.²⁴⁴ In a manner like the role of p38 in facilitating epithelial-mesenchymal transition (EMT) during the progression of colorectal cancer, the activation of STAT3 has been observed to increase the mesenchymal phenotype in many cancer cell types.245, 246, 247 Researchers have recently made a noteworthy finding indicating that the administration of polydatin to HCCML3 cells resulted in a notable decrease in the levels of phosphorylated STAT3, AKT and JAK1 expression. However, it was observed that the expression of p-p38 or p38 remained unaffected by this therapy.¹⁶¹ According to previous research, the potential impact of polydatin on intracellular ROS (reactive oxygen species) levels may be mitigated due to the involvement of the protein p38 in the regulation of oxidative stress.²⁴⁸ Previous research has demonstrated a robust link between the expression levels of FOXO1 and the EMT process in hepatocellular carcinoma (HCC).^249,250 FOXO1, belonging to the forkhead family, has a diverse range of roles including cell cycle progression, glucose metabolism, cellular differentiation, and proliferation.²⁵¹ It was discovered that the STAT3/JAK1 and AKT/PI3K signalling pathways' downstream genes included FOXO1.^252,253 Results suggested that polydatin may regulate FOXO1 to control HCC cell apoptosis (Fig. 9), EMT-associated invasion and migration, and limit cell proliferation (G2/M arrest). Thus, FOXO1 expression was measured, and it was discovered that polydatin treatment increased FOXO1 expression in HCCLM3 cells. The result of the study indicates that the upregulation of FOXO1 expression, mediated by the STAT3/JAK1 and AKT/PI3K signalling pathways, may contribute to the potential therapeutic effects of polydatin¹⁶¹.

Fig. 9.

Mechanism of polydatin in Hepatocellular carcinoma: In hepatocellular carcinoma (HCC) cells, polydatin treatment induces significant molecular changes. It inhibits Akt activation, promoting FOXO1 expression while downregulating N-cadherin and upregulating E-cadherin. These alterations inhibit cell invasion, proliferation, and migration while modulating apoptotic pathways. Additionally, polydatin increases Bax expression and decreases Bcl-2 expression, activating caspase 3 and caspase 9 and initiating programmed cell death, ultimately inhibiting HCC cell growth and survival. [↑ = upregulate, ↓ = downregulate, ^┬ = Inhibit, ↑↓ = regulate].

The findings of the study indicate that the administration of polydatin resulted in an elevation in the activity of caspase-3, as well as an increase in the levels of caspase-3 protein expression. Additionally, the levels of caspase-9 and Bax protein were found to be enhanced, whilst the expression level of Bcl-2 protein was observed to be reduced (Fig. 9).²⁵⁴ The process of cancer cell migration and invasion is widely recognized as a significant factor in cancer metastasis.²⁵⁵ Previous studies have demonstrated that polydatin can block the invasion and migration of hepatocellular carcinoma (HCC) cells, as assessed using wound healing assay and transwell invasion assay.⁶⁸ The association between the pathophysiology of hepatocellular carcinoma (HCC) and abnormal activation of Wnt/beta-catenin signalling has been demonstrated.256, 257, 258 The administration of polydatin has been observed to effectively inhibit the activity of the Wnt/beta-catenin signalling pathway in hepatocellular carcinoma (HCC) cell lines, as reported in a previous study. In vivo experiments conducted by the scientists showed that polydatin hindered tumour growth by inducing apoptosis, suppressing proliferation, and enhancing TUNEL activity and caspase-3 while decreasing Ki-67 expression, as revealed by the analysis of resected tumour tissues.⁶⁸

Another study also provided evidence that polydatin has inhibitory effects on the migration, invasion, and proliferation of hepatocellular carcinoma (HCC) cells, as well as the induction of apoptosis. Additionally, it was observed that polydatin downregulates the expression of several genes that promote cell development, such as cyclin D1, β-catenin, survivin and MYC.²⁵⁴

Studies have shown that PD has cytotoxic and chemotherapeutic medication resistance against a wide range of agents. For instance, the glucose competitor 2-DG (2-deoxy-d-glucose) which inhibits glucose breakdown and prevents the development of cancer cells, but its use in clinical settings at relatively large dosages results in adverse cardiac toxicity.²⁵⁹ PD and 2-DG together, however, reduced this detrimental effect on hearts and other vital organs.²⁶⁰ In a model of xenograft mice, PD increased the anticancer effects of 2-DG by blocking the AKT/PI3K signalling pathway.²⁶¹

According to a different study, polydatin administration decreased the glycolytic pathway, significantly improved cardiac signs in an animal experiment, and increased the susceptibility of breast, colon, and pancreatic cancer cells to chemotherapeutic medications such as lapatinib, DDP, and DOX.²⁶² A longer lifespan has been linked to PD and it also displays antioxidant activity.²⁶³ Although considered a powerful and all-purpose antioxidant, PD's function in mediating oxidative state varies on the kind of cell. For example, PD reduced oxidative stress in cardiomyocytes and lowered the risk of myocardial infarction, but it increased oxidative stress and accelerated apoptosis in nasopharyngeal cancer cells.^69,264 Researchers tested the anticancer effect of PD using HepG2 and SK-HEP1 liver cancer cells as well as HL-7702 normal liver cells. They found that PD dramatically reduced the cytotoxicity of HCC cells while specifically inhibiting the proliferation of HCC cells. Experimental results, however, revealed that normal cells exhibited relatively high toxicity against the generic chemotherapeutics DDP and DOX, in contrast to HCC cells. Thus, scientists were very much in favour of PD being used in clinical settings as a cancer treatment. Researchers found multiple signalling pathways and target genes affected by PD, including spindle midzone formation, which is crucial for mitosis, using RNA-seq analyses in PD-treated HepG2 cells. A few investigations have found that PD therapy reduced the expression of five genes that regulate spindle fibre growth, which leads to abnormal spindle assembly and increased susceptibility to apoptotic stimuli.²⁵⁹ Moreover, PD interfered with several metabolic processes, including fatty acid production and breakdown; however, it is yet unknown whether PD was directly or indirectly responsible for these changes. The study leads to the conclusion that spindle formation is the main biological mechanism that PD targets, and that increased expression of the five genes is significantly connected with poor clinical outcomes in HCC patients.²⁶⁰

4. Effect of polydatin in combination with other drugs on different cancers

4.1. Polydatin in combination with 5 FU

Researchers have discovered that the combination of radiation therapy with PD greatly increases the removal of colorectal cancer cells, inhibits the cancer's growth, and induces apoptosis.¹⁵⁶ Moreover, PD can both accelerate and prevent Lgr5+ CSC apoptosis. According to reports, Lgr5, a surface marker of CRC stem cells, is present in 74–85 % of CRC cases.^136,256 It is widely accepted that several signalling pathways, which are intimately linked to radiation sensitivity, mediate the formation of intestinal stem cells. These pathways include BMP, PI3K, Notch and Wnt signalling.^265,266 By focusing on the BMP signalling system, researchers have demonstrated that PD can reduce the radioresistance of CRC stem cells. They observed the activity and proliferation of CSCs by treating them with a BMP signalling inhibitor called K02288. The outcome of the study revealed that the addition of K02288 minimized the suppressive effects of combined PD and radiotherapy on CSCs' proliferation and these results suggest that PD controls CSC radiosensitivity through the BMP signalling pathway.¹⁵⁶

The researchers conducted a study and found that polydatin has the potential to enhance the effects of conventional anticancer drugs like 5-FU and counteract resistance in colon cancer.⁸⁷ High levels of TYMS and p-P53 expression are associated with 5-FU resistance, whereas decreasing TYMS and increasing p-P53 can improve colon cancer's responsiveness to chemotherapy.^267,268 Interestingly, polydatin had the reverse effect when given to 5-FU-R cells, increasing TYMS and lowering p-P53. Furthermore, the apoptotic signals, cytochrome c, cleaved caspase 3 and 9 and BAK, were all significantly increased by polydatin, indicating that it may have a different mechanism from TYMS and P53 for increasing chemosensitivity in 5-FU-R cells.⁸⁷

4.2. Polydatin in combination with PLGA-NPs

The study examined the potential use of polydatin to reverse oral carcinogenesis, a form of cancer that affects the neck and head.^269,270 Unfortunately, polydatin's slow rate of dissolution and low water solubility limit its therapeutic applicability. In response to this problem, the application of polymer-based nanoparticles has become more significant in the treatment of cancer because they improve the therapeutic efficacy and solubility of anticancer medications in aqueous environments.²⁷¹ The study investigated the chemopreventive role of PLGA-encapsulated polydatin in hamsters' buccal pouch carcinogenesis induced by DMBA, including inflammation, cellular proliferation, and angiogenesis. The use of POL-PLGA-NPs reduced the incidence and size of tumours in hamsters exposed to DMBA, according to the data. Additionally, POL-PLGA-NPs enhanced phase II detoxifying enzyme levels while decreasing phase I enzymatic levels of Cyt b5 and Cyt P450, and they decreased the loss of antioxidants in cells and tissues caused by DMBA. The results of the study indicate that polydatin may one day be used as a chemopreventive drug against oral cancer. The use of polymer-based nanoparticles may improve the therapeutic efficacy of anticancer medications.²⁷²

4.3. Polydatin in combination with doxorubicin

Researchers found that polydatin caused the doxorubicin-resistant osteosarcoma cells to undergo apoptosis and decreased their ability to proliferate. In these cells, polydatin was similarly found to dramatically and dose-dependently lower TUG1 expression. To investigate the function of TUG1/Akt signalling in doxorubicin-resistant osteosarcoma cells treated with polydatin, scientists created TUG1-targeting shRNA and PCR-amplified TUG1, which were subsequently transfected into the cells. Polydatin's anti-proliferative and apoptosis-inducing capabilities were shown to be boosted in TUG1 knockdown cells, whereas these effects were lessened in TUG1 overexpression cells, according to the study. According to a Western blotting study, polydatin therapy decreased Akt phosphorylation expression in TUG1 knockdown cells but not in TUG1 overexpression cells. This suggests that polydatin treatment of doxorubicin-resistant osteosarcoma cells requires suppression of TUG1/Akt signalling²⁷³

4.4. Polydatin in combination with 2-DG

Researchers discovered that 2-DG and PD both lowered the viability of MCF-7 and 4T1 breast cancer cells (Fig. 5). When combined, they were more efficient at inducing apoptosis and reducing cell proliferation and migration than when applied alone.¹⁶² Hexokinase phosphorylates the glucose analogue, 2DG, which competes with 6phosphate glucose (6 PG) to limit glycolysis, leading to cancer cell death from ATP depletion.^274,275 AKT activation is commonly seen in a variety of malignancies and appears to be closely related to aerobic glycolysis, proliferation, and invasiveness. ROS are a crucial mediator of the mixture's actions on the PI3K/AKT pathway. It has been observed that in cancer cells, ROS downregulates AKT.^276,277 It's significant to remember that HIF1 is increased in cancer cells due to AKT activation.²⁷⁸ It was found that co-treatment with 2DG and PD increased HIF1-α in breast cancer cell lines by inhibiting the AKT/PI3K pathway. The increased expression and activity of glucose transporters such as Glut1, which is regulated by HIF-1 α and is the most overexpressed Glut with a 10- to 12-fold higher expression in tumour cells than in normal cells, have a significant impact on the rate of glycolysis.^279,280 ZHANG et al. claim that the combination of 2-DG and PD inhibited glycolysis, providing a possible treatment option for breast cancer patients.¹⁶²

Fig. 5.

The combination therapy using PD (polydatin) and 2DG (deoxy-d-glucose) on Breast Cancer. Two-DG alone can competitively block HK2's glucose-to-6P-G conversion. Cell glycolysis decreases, ATP production declines, and apoptosis occurs. 2 DG drives pro-survival PI3K/AKT signalling. By reducing intracellular ROS, PD blocks 2DG-induced PI3K/AKT activation. When PI3K/AKT is suppressed, HIF1 transcription is downregulated, inhibiting the pro-survival signal. Polydatin slows Creb phosphorylation, which lowers cyclinD1 and cyclin A production and stops cell cycle progression at the S phase, causing breast cancer cells to die by apoptosis.

4.5. Polydatin in combination with brusatol

In the context of triple-negative breast cancer (TNBC), a formidable subtype of breast cancer associated with poor prognosis and limited treatment options, the study explores the potential of combining two natural compounds, polydatin (PD) and brusatol (BRU), as an alternative therapeutic approach.^121,281 TNBC's aggressive nature, poor prognosis, and drug resistance make it challenging to treat effectively with existing chemotherapy methods. Chinese herbal medicine, known for its low toxicity and ability to reverse drug resistance, emerges as a promising avenue for cancer treatment.²⁸²

Previous studies have demonstrated the individual anti-tumour activities of BRU and PD. BRU, in combination with other drugs, has shown synergistic effects, inhibiting migration and invasion of TNBC cells.^283,284 Similarly, PD has exhibited anti-cancer effects, inducing pyroptosis in TNBC.¹⁴⁰ Given the benefits of herbal extracts and the limitations of traditional chemotherapeutic drugs, the study investigates the combined effect of BRU and PD on TNBC. The research optimizes the treatment method, demonstrating that the combination of BRU and PD effectively inhibits the Nrf2/HO-1 and NQO1 pathways, induces the generation of reactive oxygen species (ROS), and inhibits TNBC cell proliferation. In animal models, the treatment regimen is refined, emphasizing the therapeutic advantage of BRU + PD by reducing dosage and administration frequency.284, 285, 286, 287, 288

Under normal physiological conditions, the body's redox system maintains balance. However, disruptions in ROS levels can significantly impact tumour growth during cancer development.²⁸⁹ The study finds that BRU + PD reduces the proliferative capacity of TNBC cells and elevates ROS levels, contributing to the potent antiproliferative effect. The role of ROS in tumour progression is complex, as both extremely high and low levels can influence signalling pathways. The combined effect of PD and BRU on ROS levels and tumour cell growth through other signalling pathways warrants further exploration.²⁹⁰

Nrf2, a transcription factor, plays a crucial role in responding to oxidative stress. High Nrf2 expression can protect tumour cells from chemotherapeutic damage, making it a key target in cancer therapy.²⁹¹ The study reveals that the combination of BRU + PD downregulates Nrf2 expression, inhibits the antioxidant response, and downregulates downstream target genes such as HO-1 and NQO1. This inhibition of Nrf2 expression increases ROS levels, ultimately inhibiting TNBC cell proliferation.²⁹² The study suggests that PD might inversely regulate Nrf2 expression by influencing G6PD, a key enzyme in cancer cell metabolism.²⁹³ Further research is needed to unravel the intricate signalling pathways involved in this combined therapeutic approach.

5. Conclusion

In conclusion, Polydatin (PD) emerges as a versatile and potent anticancer agent with multifaceted pharmacological activities. Derived from Polygonum cuspidatum and also known as 3-O-β-D-resveratrol-glucopyranoside, PD has long been utilized in traditional Chinese medicine for its diverse therapeutic properties. The extensive exploration of PD's effects on various cancer types reveals its significant potential as both a standalone treatment and in combination with other drugs. PD showcases specific anticancer mechanisms tailored to distinct cancer types. In ovarian cancer, it effectively impedes cell migration and proliferation while influencing the expression of the PI3K protein. For lung cancer, PD reduces malignancy by targeting caspase 3, arresting cells at the S phase, and inhibiting the NLRP3 inflammasome through NF-κB pathway downregulation. Breast cancer experiences disrupted cell cycles, reduced VEGF, and countered ROS upon PD treatment. The preventive effects of PD on cervical cancer involve the regulation of EMT, apoptosis, and the C-Myc gene.

Moreover, PD exhibits promising synergistic effects when combined with other drugs. In colorectal cancer, the combination of PD with 5-FU enhances radiation therapy outcomes, inhibits cancer growth, induces apoptosis, and addresses resistance. PD combined with PLGA-NPs demonstrates chemopreventive potential against oral cancer by improving therapeutic efficacy and solubility. In doxorubicin-resistant osteosarcoma cells, PD induces apoptosis and inhibits proliferation through TUG1/Akt signalling suppression when combined with doxorubicin. The combination of PD with 2-DG enhances antitumor effects on breast cancer by inhibiting glycolysis. The exploration extends to the promising combination of PD with brusatol (BRU) for triple-negative breast cancer (TNBC). The synergistic effects of BRU + PD inhibit the Nrf2/HO-1 and NQO1 pathways, elevate reactive oxygen species (ROS) levels, and effectively reduce TNBC cell proliferation. This alternative therapeutic approach addresses the aggressive nature and limited treatment options associated with TNBC, showcasing the potential of herbal extracts in cancer treatment.

In light of the growing interest in phytomedicine, PD stands out as a promising anticancer drug due to its potential to modulate numerous signalling pathways associated with cancer development. Its antioxidative properties, apoptosis induction, and interference with oncogenic pathways contribute to its anticancer efficacy. The review emphasizes the need for in-depth investigations into PD's mechanisms of action and advocates for carefully monitored human studies to determine its therapeutic efficacy in clinical settings. Overall, this review supports polydatin's role as a valuable component in the advancement of novel approaches for cancer prevention and treatment, further emphasizing the need for continued research to harness its full therapeutic potential.

6. Limitations and future directions

While Polydatin (PD) exhibits promising anticancer effects in preclinical and in vitro studies, its translation to clinical settings requires rigorous validation through well-controlled human trials. This includes assessing safety, dosage, and efficacy across diverse patient populations. Understanding the specificity of PD's mechanisms for different cancer types is crucial, necessitating further investigation into its interactions with specific molecular targets and pathways. Long-term safety, especially in combination with other drugs, needs thorough examination to assess potential side effects and impacts on normal cell function. Optimizing formulations and delivery systems to enhance PD's bioavailability and efficacy is essential. Investigating resistance mechanisms, particularly in combination therapies, is imperative for guiding strategies to overcome or prevent resistance. In future directions, exploring combination therapies with a wider range of anticancer drugs and personalized medicine approaches based on biomarker identification is warranted. Large-scale clinical trials considering cancer stage, genetic variations, and patient-specific characteristics are necessary to establish PD's effectiveness across diverse populations. Additionally, detailed pharmacokinetic studies and exploration of PD's efficacy in rare cancers can uncover new therapeutic possibilities. Integrating patient-reported outcomes in clinical trials can provide valuable insights into its overall impact on patients' quality of life. Addressing these limitations and pursuing future directions will further establish PD's role in cancer therapy and contribute to the development of more effective and personalized anticancer treatments.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

PD

– Polydatin

CRC

– Colorectal cancer

CDK

– Cyclin-dependent kinase

DOX

– Doxorubicin

EGFR

– Epidermal growth factor receptor

EMT

– Epithelial-mesenchymal transition

ERK

– Extracellular signal-regulated kinases

ROS

- Reactive Oxygen Species