Anti-cancer perspectives of resveratrol: a comprehensive review

ABSTRACT

Resveratrol (RVT) is well known for its chemo-preventive and therapeutic attributes against the various kinds of cancers such as breast, prostate, pancreatic, oral, brain, lung and liver. It has been found to inhibit glioblastoma cell growth, declining uPAR and its mediator ERK1/2, inhibiting the cell lines (EC-9706) growth and ADAM9 expression, up-regulating the lncRNAs and PPARγ, inhibition of MTA1 to modulate oncogenic miR-34a, miR-22 and miR-17, enhance the E-cadherin expression and decreased the expressions of Twist1 and vimentin, inhibiting ADAM9 expression, downregulation of ATP2A2 and ATP2A3 genes expressions in different breast cell lines, reduction in IL-6 and COX-2 expression, inhibition of Tax activity of LTR and HTLV-1 in SIRT1 deacetylase, suppression of epithelial-to-mesenchymal transition (EMT) and eEF1A expression and fracas interactions between TEAD and YAP and activation of Hippo/YAP signalling. Consequently, it can be suggested that RVT is a promising agent for treating aforementioned cancers due to its curing characteristics.

KEYWORDS:

• Anti-cancer activity
• cancer stages
• bioactive compounds
• medication via resveratrol
• chemopreventive

1. Introduction

The diversity in climate and significant alteration in the human life style due to modernization and mechanization have revolutionized the world to the contemporary era. The diversification in lifestyle has also led to the number of diseases, i.e. cardiovascular diseases, cancers, diabetes, allergies, strokes and Alzheimer’s diseases, in populations, globally. Cancer is one of these most common disorders that can be defined as the growth of abnormal cells with the capability of invasion and spreading to other body parts. The genes responsible for the conversion of normal cells into cancer cells also stimulate their growth (Wani et al., 2023). The genetic mutations in 90–95% of cancers are occurred due to environmental influences and 5–10% of cancers are because of inheritor genes. Various remedies are being developed in different fields such as chemotherapy, allopathy, pharmaceutical and nutraceutical treatments to cure these various kinds of cancers. In these concerns, different phytochemicals, i.e. flavones, isoflavones, phenolic acids and stilbenes have also been studied. Stilbenes developed in response to different stressing environments such as during fungal infections, viral diseases and ultraviolet (UV) radiations and can be extracted from the various parts of conventional and unconventional plants (Hosseini & Ghorbani, 2015). Resveratrol (RVT) chemically known as 3,5,4-trihydroxystilbene belongs to the stilbenes family and naturally present in various plants and natural foods, i.e. red wines (0.98–1.80 mg/L), boiled peanuts (5.1 μg/g), peanut buffers (0.31 μg/g), grape skin (50–100 μg/g), grape juice (4 mg/L) and blueberries (trace amounts) (Xiao et al., 2019; Zhao et al., 2021). Resveratrol consisted of two phenolic rings, one ring attached with ortho double hydroxyl groups and other with para-hydroxyl group. Furthermore, 2-benzene rings are also attached via double bond which aids in the formation of trans- and cis-configured isomers. The trans isomer is considered as most biologically active and most abundant compound (Xiao et al., 2019). RVT along with its analogues depicts good interface with the targeted receptors by creating hydrophobic interactions with amino acids and developing hydrogen bonds via hydroxyl groups at the binding sites. Various pathogenic targets are inhibited by producing the stable complexes and binding geometry of RVT compound (Kataria & Khatkar, 2019).

RVT became popular in 1997 due to its anti-cancer properties. Later on, researchers and scientists started to pay attention to resveratrol because of its prominent potential in the treatment of cardio-protective activities, tumorigenesis and inflammation. Currently, RVT has been known for its wide range of biological effects such as anti-diabetic, neuro-protective, cardio-protective, antioxidant, anti-inflammatory and anti-proliferative activities. It also showed the anti-cancer and anti-aging activities (Ahmadi & Ebrahimzadeh, 2020; Almeida et al., 2021; Rauf et al., 2018; Tian & Liu, 2020; Zhao et al., 2018). The higher doses of RVT are capable to enhance the lifetime of mammals (Xiao et al., 2019). Furthermore, RVT reported to show the redox biology, modulation of mitochondrial functions and dynamics in both in vivo and in vitro study trials. RVT also plays a prominent role in the attenuation of mitochondrial impairments produced by specific stressors (Jardim et al., 2018). According to a study, RVT prevents the initiation, promotion and progression through ERK1/2 and AKt signalling pathways in carcinoma cells of renal cells (Zhao et al., 2018). Figure 1 is elaborating the effect of RVT at different cancer growth stages.

Figure 1. Common mechanism of resveratrol in management of cancer.

The current study is planned to review the various aspects of RVT such as antioxidant properties and various mechanisms against different cancers including brain, oral, oesophageal, pancreatic, prostate, liver, lung, kidney, breast, skin, blood, Ovarian and rectum/colon cancer due to its therapeutically and biological activities. Various strategies used to treat the large family of cancers by using RVT (potent medicinal agent) are given in Table 1.

Table 1. Role of resveratrol in management of various cancers by using different strategies.

Bioactive compound formulations	Cancer types	Cancer models	Main results	References
Conjugated resveratrol with low molecular weight amphiphilic mPEG-PLA	Subcutaneous melanoma B16-F10	Mouse model C57BL/6J	Reduction of tumour growth, enhanced anti-cancer effect of resveratrol	(Yee et al., 2022)
Resveratrol nano-formulation	Skin cancer	SK-Mel-28 and Colo-38	NF-kB signalling pathway retardation	(Cosco et al., 2015)
		B16F10	Greater inflammatory infiltrate of melanoma tumour and necrotic area	(Carletto et al., 2016)
		A375	Reduction of cell division	(Wang et al., 2017)
RES006 nesveratrol analogue	Human hepatoblastoma	HepG2	ER stress signalling, upregulate pEIF2α; ATF4; CHOP	(Heo et al., 2018)
		HepG2	ER stress signalling, upregulate pEIF2α; ATF4; CHOP	(Park et al., 2017)
Resveratrol nano formulation	Breast cancer	MCF-7	Deactivation of ERK1/2 and PI3K/AKt and activation of HO-1 signalling stream	(Park et al., 2016)
		MCF-7	Introduction of apoptosis, cell proliferation is decreased, and reduction of PI3K/AKt pathway	(El-Far et al., 2018)
		T47D and MCF-7	Introduction of apoptosis & retardation of HRG-β1 signalling pathway	(Abdel-Latif et al., 2015)
		MDA-MB-231	Introduction of apoptosis and Wnt signalling pathway	(Wang et al., 2017)
Resveratrol nano formulation	Prostate cancer	PC3, C4-2B, and LNCaP	NF-kB pathway inhibition	(Singh et al., 2018)
		LNCaP	Increased apoptosis	(Nassir et al., 2018)
		DU145	Increased apoptosis	(Saralkar & Dash, 2017)
		PC-3	Increased apoptosis	(Chen et al., 2016)
Resveratrol, coenzyme Q10	Breast cancer	Dimethyl-benz[a]anthracene-induced breast cancer model	This system increased bioavailability of coenzyme Q10 and resveratrol. More capacity to reduce tumour proliferation than the combination of free resveratrol	(Jain et al., 2017)
Resveratrol		Co-delivery of pemetrexed, Mannose-grafted albumin-QDs	Breast cell cytotoxicity (in vivo), and tumour growth reduction (in vivo), inhibition of angiogenesis is greater than free drugs and promotion of apoptosis	(Zayed et al., 2019)
Resveratrol	Gastric cancer	SGC7901 and BGC823 (Cell lines of gastric cancer)	Inhibition/reduction of MALAT1-induced EMT	(Yang et al., 2019)
Resveratrol		SGC7901 cells	cell cycle arrest in gastric cancer cells and increased cell death by apoptosis	(Kim et al., 2019)
Resveratrol nano formulation	Colon cancer	BGC823 and SGC-7901	Stimulation of cell death by apoptosis and cell necrosis PI3K/PTEN/Akt pathway	(Hu et al., 2019)
Resveratrol nano formulation		HT-29 and LS147T	Stops the NF-kB signalling pathway	(Summerlin et al., 2016)
Resveratrol nano formulation		RAW 264.7 and Caco-2	Enhanced apoptotic cell death decrease of IL-6 and NF-kB	(Juère et al., 2017)
Resveratrol nano formulation	Liver cancer	SMMC 7721 and L02	Apoptosis induction and reduction of PI3K/Akt signalling pathway	(Wu et al., 2017)
Resveratrol and P53 gene with novel cationic-peptide liposomal nanocarrier	Breast and cervical cancer	-	This system enhanced tumour suppression and apoptosis induction thanp53 gene liposomes or resveratrol liposomes	(Xu et al., 2019)
Resveratrol with pemetrexed	Lungs cancer	A549 cells	Greater cellular 6uptake and increased cytotoxicity of resveratrol to cancer cells	(Abdelaziz et al., 2019)

2. Antioxidant potential

The resveratrol was first time recognized as a natural antioxidant clearly (Zini et al., 1999). The study provided three different mechanisms about antioxidants, i.e. (i) prevention of lipid peroxidation produced as a product Fenton reaction, (ii) scavenging the oxygen, produced in mitochondrial cells and (iii) fighting with coenzyme Q to reduce the complexes of oxidative chains, at the site of reactive oxygen species (ROS) synthesis. According to some studies, RVT is capable to scavenge both OH and O₂ radicals (Leonard et al., 2003; Losa, 2003). All the cells of the body have various defense mechanisms that involve different enzymes such as superoxide dismutase (SOD), catalase, glutathione reductase and glutathione peroxidase to save the tissue from the various deleterious effects of ROS. RVT aids in maintaining the intracellular antioxidants concentrations of the biological system. According to a study, stilbene maintained the glutathione contents in isolated mononuclear cells of peripheral blood (ex vivo) from healthy subject having oxidative impairment occured by 2-deoxy-D-ribose. Olas et al. (2004) reported that RVT significantly reduced oxidation of proteins at their thiol group in platelet cells of human blood. Likewise, RVT stimulates an enhancement in glutathione levels depending on concentration levels H₂O₂-activated human lymphocytes. In a research, it was found that RVT improved concentrations of various antioxidant enzymes, i.e. glutathione reductase, G. S-transferase and G. peroxidase (Yen et al., 2003). RVT is capable to scavenge many free radicals. The antioxidant attributes of RVT in vivo model depicted its impacts on gene regulators. Resveratrol prevents ROS production which is mediated by NADPH oxidase by down regulation of expression and activities of oxidases. RVT stimulates mitochondria biogenesis to decrease the mitochondrial superoxide generation. RVT inhibits the production of super oxides from detached endothelial nitric-oxide synthase by up-regulating the GTP cyclohydrolase I (tetrahydro-biopterin synthesizing enzyme). Moreover, resveratrol enhances the functions of different antioxidant enzymes. Nuclear factor-E2-related factor-2 and protein/histone deacetylase sirtuin 1 mediate the resveratrol effects on gene regulations (Xia et al., 2017).

3. Resveratrol mechanism for anti-cancer activity:

One of the root causes of death in the globe is cancer. The standard first-line treatments for cancer patients include radiotherapy and chemotherapy. Nevertheless, despite their deadly side effects, most cancer cells become resistant to both radiotherapy and chemotherapy. This inspired researchers to look for more efficient alternatives with less side effects. Due to its extensive biological effects, resveratrol, a naturally occurring polyphenolic phytoalexin, has received a lot of attention recently (Elshaer et al., 2018). Resveratrol's molecular mechanisms included genesis of cell metabolism and multiprotein complexes; cytoplasmic protein tyrosine kinase signalling (integrin, cytokine and developmental pathways); cell proliferation and genome instability; hormone signalling and immune surveillance; cell signalling via transforming growth factor-β super-family; signalling mechanisms related to receptor tyrosine kinases and extracellular growth factors. In adjuvant therapy, affiliated with cisplatin and 5-fluoruracyl, resveratrol had synergistic or/and additive effects, escalating the chemo-sensation of cells having cancer. Resveratrol also demonstrated a promising role in the fight against multidrug resistance. Resveratrol has been highlighted as a good, diversely targeted anti-cancer drug that is useful for both prevention and treatment of cancer because of its potential to act on several mechanisms concurrently (Varoni et al., 2016).

It is believed that RVT can target many molecular signalling pathways in the treatment of cancer. The tumour cells resistance to chemotherapy is one of the challenges in cancer treatment. The invention of new synthetic anti-tumour medications is the result of this issue. However, using a high dose of an anti-cancer drug lessenes its effectiveness in subsequent treatments. Moreover, the dynamic progression of tumour cells involves a number of pathways, necessitating combination therapy to suppress cancer cells. Epidermal growth factor receptor (EGFR) appears to be regulated by uPAR (urokinase-type plasminogen activator receptor). Tumour cells that overexpress uPAR are more resistant to chemotherapy. RVT administration decreases uPAR and its downstream mediator ERK1/2, which makes oral squamous cell cancer (OSCC) more susceptible to chemotherapy (Hao et al., 2013). Research on the regulation of resveratrol by apoptosis-related factors in nude mice using a A431 xenograft of human skin squamous cell carcinoma. Increasing evidence shows that RVT activates the co-suppressor MIR to promote apoptosis in cancer cells. By increasing the miR-122-5p expression, which causes the initiation of apoptosis and lower cancer cell viability, subjection to RVT boosts the chemotherapy potential. Epithelial–mesenchymal transition (EMT) is a factor in the growth and invasion of tumour cells. In cancer therapy, EMT inhibition is crucial. Stimulating the tumour suppressor Rad9 through administration of RVT, significantly reduces the proliferative and invasive properties of the lungs and breast cancer cells. These results show that RVT can control the pathways having signals involved in malignant cancer formation, and its regulation can be intended as a viable method for treating tumours. Notably, there appeared efforts to recognize these signalling pathways as well as their upstream and downstream moderators because they are thought to play a role in the malignity of GC cells. Increasing evidence shows that aberrant miR expression is linked to the emergence of cancer (Knower et al., 2014). Similar events happen in the story of GC. To guarantee their survival and proliferation, GC cells appear to downstream the miR-27b-3p expression via increasing the expression of GSPT1. According to Junco et al. (2013), the PI3 K/Akt signalling pathway stimulates EMT, which aids in the progression of GC cells. Importantly, UFM1 inhibits PI3 K/Akt molecular signalling, which is linked to reduced GC cell migration. Non-protein type coding RNA molecules having a length of 200 nucleotides are known as long noncoding RNAs (lncRNAs). According to reports, lncRNA dysregulation causes the development of cancer. LncRNAs have the ability to both lessen and increase the malignity of cancer cells. According to one study, lncRNA HOTAIR can increase the encroaching of GC cells by activating the RhoA and CXCR4 signalling mechanisms, although lncRNA GAS5 is linked to reduced GC cells metastasis by targeting(Ashrafizadeh et al., 2021). Other molecular pathways connected to GC malignancy include Nrf2 (nuclear factor erythroid 2-related factor 2) and MAPK (mitogen-activated protein kinase) (Kim et al., 2016). The general mechanism of RVT in the management of cancers is given in Figure 2.

Figure 2. Effect of resveratrol at different stages of cancer.

4. Utilization of resveratrol in management of various cancers

4.1. Oral cancer

Oral cancer prevalence is becoming a common tumour with higher mortality rates. Oral squamous cell carcinoma (OSCC) is considered among the most destructive and prevailing neck and head cancers causing high mortality and morbidity. The traditional methods used to cure have various side effects and are not enough to improve the survival rate. Thus, scientists and researchers are seeking for the unique therapeutic adjuvants and compounds as a remedy of cancer and fortunately natural bioactive compounds have found to have prominent potential as anti-cancer agents (Angellotti et al., 2023).

In oral cancer, impact of RVT on lipid metabolism depicted that the significant reduction in lipogenesis occurred by down regulation of epidermal fatty acids binding proteins (EFABP) and transcripted gene, i.e. sterol regulating elements binding protein 1 (SREB-1). The cell survival signals mediated by SREBP1 were inhibited due to RVT-induced autophagy. The animal xenograft model study resulted that the RVT significantly reduced the progression of oral cancer cells without adverse effects (Fukuda et al., 2022). The formulation of RVT-loaded liposomes proved to have significant effects in both in vivo and in vitro OSCC experiments which introduced the formation of RVT-loaded drug delivery mechanisms to cure target sites in oral cancer treatment (Angellotti et al., 2023). RVT stimulates mitochondrial biogenesis upgrading the bioenergetics status of mitochondria and up regulates antioxidant enzymes present in mitochondria which reduce the production of ROS. The study revealed that RVT improved the brain mitochondrial functions by increasing oxygen consumption rate of brain cells (glial and neuronal) resulting in higher ROS production (Jardim et al., 2018). RVT has higher ROS-scavenging activities and acts as an antioxidant to depict its anti-cancer effects through cell signalling systems. Moreover, resveratrol revealed the anti-cancer effects due to epigenetic variations such as down regulation of circular RNAs (circRNAs), micro noncoding RNAs and long noncoding RNAs. It moderates the expressions of different agents involved in the ROS-scavenging anti-cancer systems by reducing the activities of oncogenic ncRNAs and enhancing the activities of cancer suppressive ncRNAs (Hayakawa et al., 2022). In a study, the combination of RVT and Quercetin (Quer) in non-cancerous HEK-293 cells, and SCC-15 and Cal-33 oral cancer cells were investigated. The RVT and Quer in combined form (10 μM each) modulated the DNA damage, cellular growth, cell death and cell cycle arrest (S-phase) in Cal-33 cells and depicted no effect on HEK-293 cells. The separate and combined treatments of RVT increased the ratio of transcription initiation and suppression histone mark and also dysregulate the Histone deacetylase 1, 3 and 8. The finding suggested that RVT utilization can be a perceptive approach against oral cancer (Singh et al., 2020). The anti-metastatic activity of RVT was investigated to explore the cisplatin preventing human OSCC cell lines (CHOC). The RVT dose (25–75 µM) during 24 h treatment reduced the relocation and invasion capabilities of CHOC cells depending on the dose. The dose of 50 µM RVT reduced the activities of phosphorylated analogues of p-38, ERK, MMP-9 and MMP-2. The study resulted that resveratrol drug delivery suppressed the metastatic activities in oral cancer cells significantly (Chang et al., 2021). A systematically study revealed the impact of resveratrol nanoparticles (RVT-NPs) in reduction of cancer stem-like cells (CSCs) which are induced in cells by cytokines. The conditioned medium (CM) enriched with M1-like macrophages (MLMps) was created by inducing fixed concentrations of LPS and PMA in THP-1 cells separately and co-culture of THP-1 and H-357 cells. These MLMPs enhanced the formation of various cytokines, i.e. IL-1β, IL-6 and TNF-α. Then CSCs enriched conditions were developed by adding co-cultured CM enriched with cytokines to the cancer cells and CM enriched with cytokines in THP-1cells to the patient of customized oral cancer cells. It was resulted that the stemness-mediated CSCs are totally cytokines reliant phenomena and RVT-NPs played a prominent role in prevention of oral cancer during ex vivo, in vivo and in vitro models (Pradhan et al., 2021). In a study, CSCs-augmented media was generated through incubation of CAFs with H-357 cells and cytokine-augmented media conditioned with CAFs. CSCs-augmented conditions were also created after incubation of CAFs-conditioned population to the oral cancer cells derived from cancer patients. The results concluded that the growth of CSCs is IL-6 and CXCL-12-dependent and resveratrol-based nanoparticles hinder the metastasis and carcinogenesis by preventing IL-6 and CXCL-12 and development in ex vivo, in ovo, in vitro and in vivo studies (Pradhan et al., 2023).

The impacts of resveratrol, tannic acid and epigallocatechin gallate (EGCG) on cytotoxicity persuaded by doxorubicin in normal oral keratinocytes of human and also their impact on doxorubicin influence in HSC-2 oral carcinoma cells of human were evaluated in a study. It was resulted that RVT along with doxorubicin additionally enhanced the cytotoxicity in both normal oral keratinocytes and HSC-2 oral carcinoma cells (Sheng et al., 2018).

A study was conducted to evaluate the impact of T4 on resveratrol-persuaded anti-proliferation in oral cancer. Resveratrol obstructed the proliferating genes and stimulated the anti-proliferation genes. During RVT treatment by cancer cells, T4 inhibited the COX-2 nuclear accretion and maintained the RVT-persuaded COX-2 in the cytoplasm. S31-201, a signal transducer and activator of transcription 3 (STAT3), as a specific inhibitor obstructed inhibition persuaded by T4 and reinstated RVT-persuaded accumulation of nuclear COX-2. RVT was capable of successive regeneration of gene expressions dependent on COX-2/p53 and anti-proliferation phenomenon by preventing the T4-induced STAT3 signal transductions along with S31-201 (Chen et al., 2019). The effects of pinostilbene hydrate (PSH), a methylated derivative of resveratrol, on anti-metastatic activities and the linked signalling pathways involving the mechanisms of HSC-3 and SCC-9 SAS cell lines of oral cancer by western blot analysis, wound healing trans well assay, zymography and MTT assay were studied. PSH suppressed the enzymatic activities of MMP-2 by reducing the regulation of protein kinases (p38)/ extracellular signal-regulated kinase (ERK1)/2 pathway. Therefore, it can be a beneficial substance for hindrance of OSCC cell metastasis (Hsieh et al., 2018).

4.2. Oesophageal cancer

The malignant cells formation in oesophagus can damage its tissue that leads towards a serious disease known as oesophageal cancer. Various factors such as Barrett’s oesophagus, use of heavy alcohol and smoking can contribute to risks of oesophageal cancer. Symptoms and signs of this cancer include difficult and painful swallowing and weight loss. RVT prevent the progression of cell lines (EC-9706) of oesophageal cancer in time and dose-dependent manners. Systematically, resveratrol prevents ADAM9 protein (kind of metalloprotease) expression in cancer cells through the ubiquitin-proteasome pathway. Furthermore, RVT along with clinical chemotherapies depicts various synergistic effects. It was suggested that RVT has prominent potential to prevent the ESCC growth and human lung cancer (LUC) by preventing expressions of ADAM9, resulting in the provision of significantly improved the mechanism for anti-cancer activities of RVT (Lin et al., 2020). Deoxycholic acid (DCA) is known as a major contributor in the carcinogenesis during reflux at the site of stomach contents entry to lower oesophagus, in oesophageal adenocarcinoma. It is very difficult to recognize the mechanisms however functions of oesophageal carcinogens can be developed to evaluate their therapeutic attributes. DCA is capable to destroy the chromosomes and synthesize ROS. It represents non-linear dose responses for DNA destruction. DCA is not capable of DNA damage induction below 100 μM but it is capable to induce DNA damage at or above the doses of 100 μM in oesophageal OE33 cells. RVT plays a key role in the reduction of DCA effects in the complete GI tract (Jenkins et al., 2008).

4.3. Pancreatic cancer (PC)

It is a disease which includes the formation of malignant cells in various pancreatic tissues. The major factors include the health history and smoking in increasing the risks of PC. The symptoms and signs of PC contain weight loss, pain and jaundice. It is very challenging to diagnose the PC at early stages. PC is considered to be the 4th most common reason behind cancer-linked deaths, with average survival rate of <6 months and only 6% of patients suffering from this cancer have the survival rate of 5 years. The symbols of PC include the short resistant, lower survival duration and poor outcomes of therapy. The poor prediction of PC is linked with locally reappearances, liver metastasis and lymph nodes and peritoneal dissemination. Various compounds consisting of small structured molecules with potential anti-cancer activities have been developed to manage the apoptosis and autophagy linked with PC treatments. These compounds mostly attack the apoptosis directly via PI3 K/Akt/mTOR and EGFR/Ras/Raf/MAPK pathways. The drugs used to cure the cancers via regulation of autophagy are divided into three categories: direct and indirect autophagy stimulators (i.e. rapamycin and resveratrol) and autophagy preventers (3-methyladenine, chloroquine). RVT persuades both autophagy and apoptosis with cytoprotective influences. However, autophagy preventer can stop the defensive autophagic effects for therapeutic attributes. Various studies depicted the autophagy obstruction causing the chemotherapy (i.e. mixture of gemcitabine/ 5FU aith metformin) effects. These drugs contain a specific clinical importance in curing PC along with different carcinomas dependent on autophagy (Selvarajoo et al., 2022). RVT plays a key role against various endocrine cancers via CSCs regulation. Accruing evidence have demonstrated that the circRNAs and long noncoding RNA (lncRNA) play a prominent role in regulating the chemosensitivity in PC. The lncRNAs play a prominent role in drug resistance of PC cells such as CASC2, SLC7A11-AS1, HCP5, HOST2, TUG1, MEG3, DYNC2H1-4, UCA1, GAS5, linc-ROR, PVT1, HOTAIR and HOTTIP. However, circRNAs, i.e. circ_0000284 and circHIPK3 help in modulation of drug sensitivity of PC cells. RVT regulates the expressions of lncRNAs and increases chemosensitivity in PCs. Hence, targeting particular cicrRNAs and lncRNAs might beneficial in reverse chemoresistance of PC cells (Xin et al., 2023).

RVT up regulates PPARγ expressions and relieves ER stress, leading to inhibition of ferroptosis induced by acrolein. The study resulted that new aspect of acrolein’s cytotoxic mechanisms on pancreatic β-cell cells and the curative impact of RVT. It is considered as SIRT1 agonist which is capable to alleviate severe acute pancreatitis (SAP), while tangible protective mechanism is still unknown. It is remarkable that the disturbance in microcirculation can be a major factor in SAP and SIRT1/FOX1 axis may control the microcirculation (Zhang et al., 2022). Triacetyl resveratrol (TCRV), a resveratrol derivative was utilized to demonstrate its effect in PC cells. Different tests were conducted by using various methods, i.e. apoptosis by terminal deoxy-nucleotidyl transferases-intermediated dUTP nick end labelling assays and cell sorting activated by fluorescence, gene experiences by reverse transcription quantitative polymerase chain reactions, impact of TCRV inhibition EMT and on pancreatic malignant cell invasions and migration by anti-miR-200 and apoptosis induction by suppressing the sonic hedgehog (Shh) pathway, and via Bcl-2 expression cyclin D1 modulation. It was reported that TCRV prevents the EMT and PC growth by targeting Shh pathways and its mediators involve in downstream signalling. TCRV hindered EMT via enhancing the stimulation of miR-200 and proved as a significant agent in the treatment of PC (Fu et al., 2019). The impact of RVT and its mechanisms were investigated in a study which resulted that the RVT hinders the invasion, migration and proliferation and suppresses the RYR2 expressions in PC cells (Jiang, Tang, et al., 2022).

Nutrient-deficiency autophagy factor 1 (NAF-1), mostly presenting mitochondrial and endoplasmic reticulum (ER) outer membranes, is a major genetic locus responsible for the regulation of autophagy and oxidative stress. NAF-1 was demonstrated in PC tissues and linked with growth of PC. RVT hindered the NAF-1 expressions resulting in tumour growth inhibition in intravenous xenograft model of PC in nude mices. Hence, RVT might be a potential anti-cancer drug by targeting the NAF-1 to cure cancer (Qin et al., 2020). Hypoxia-inducible factor-1 alpha (HIF-1α) expressed in higher levels in PC and linked with deprived prognosis. The findings revealed the ligand efficacy and binding affinity of RVT against HIF-1α utilizing silico method, and molecular dynamics simulation (MDS) execution enhanced the estimation precision of results. The RVT and HIF-1α interaction were characterized and spatial structural formations in PC therapy were provided for drug target connections (Srivani et al., 2020). RVT analogue piceatannol depicted various biological attributes, i.e. proapoptotic, anti-inflammatory, antioxidative and anti-proliferative, in different in vivo and in vitro human cancer study trials. The study revealed piceatannol reduced cell viabilities in time and dose-dependent manners (at 48 h trial, the maximum half inhibitory concentrations (IC50) was 90 µM in MIA PaCa-2 and 60 µM in PANC-1 cell lines) and resulted significant variations in expressions of protein and apoptosis linked genes. Piceatannol demonstrated the anti-cancerogenic effects on MIA PaCa-2 and PANC-1 cells, and created these effects through inducing apoptosis and proliferation suppression (Çınar Ayan et al., 2022). (E)-stilbenes derivatives of the RVT and cyclic analogues of RVT including indole nucleus and benzofuran were synthesized and assessed for their capabilities to affect the tumour progression in vitro. The analogues (2, 3, 4 and 5) of RVT depicted the higher cytotoxicity in pancreatic adenocarcinoma (MIA PaCa-2) and colon cancer (HT-29) cells in comparison to (E)-stilbenes. The indolic cyclic RVT analogue 13 illustrated 8 times greater in vitro cytotoxicities as compared to RVT in response to HT-29 cancer cells. The cyclic RVT analogues 8, 9 and 12 revealed higher cell growth inhibition in HCT-116 at 20 microM whereas 13 depicted adequate antiangiogenetic activities at 10 microM (Grau et al., 2023). The chemo-preventive and therapeutic role of RVT in PC is given in Figure 3.

Figure 3. Chemo-preventive and therapeutic activity of resveratrol in management of pancreatic cancer.

4.4. Prostate cancer

The cancer produced in the prostate is known as prostate cancer (PSC). Prostate, small gland having walnut-like shape, is present in males which excretes the seminal liquid that helps in the nourishment and transportation of sperm. The diagnosis of PSC at early stages can increase the expansion of life till 100% survival rate of 5 years. Metastasized-PSC is a basic reason behind the death of PSC. Metastasis is known to be stimulated by EMT mechanisms that altered the malignant cells epithelial properties into mesenchymal structures and obstruct the cancer growth (Khusbu et al., 2020). The impact of RVT on various mechanisms, i.e. gut microbiota regulation, inflammation attenuation, immune system modulation, autophagy stimulation, apoptosis induction, metastasis suppression, cell proliferation inhibition and enhancement of anti-cancer medicines have been extensively investigated (Wu et al., 2022; Xin et al., 2023). The nanotechnological strategies and utilization of their applications extensively to attain better oral bioavailability, improved solubility, higher stability and well-mechanized RVT excretion. The RVT-NPs significantly increased its anti-cancer attributes both in vivo and in vitro models, hence suggesting it potential approach to combat different cancers (Annaji et al., 2021).

The mechanism and impact of RVT functions in PSC cell migration and proliferation, and TRAF6 (TNF-receptor associated factor 6), a non-conventional E3-ligase, as a major RVT functional mediator to prevent the PSC cells progression and proliferation and degradation of targeted lysosomal by RVT was examined. Cell counting and MTT revealed the inhibitory effects of RVT on the proliferation and viability of PC3 and DU145 cells. Consequently, the study suggested that TRAF6 works as a mediator function of RVT to conquer PSC cells migration and proliferation, and can be used for the targeted therapies in the treatment of PSC (Khusbu et al., 2020). The impact of resveratrol-treated LNCaP cells on the synthesis of DNA altered systematically that depending on time and dose was evaluated. The RVT depicted the inhibitory effects on the synthesis of DNA in 1 h treated cells which enhanced with the increase in the dose (IC50 = 20 microM) while extension in time (from 1 to 24 h) the effect of RVT was doubled on DNA synthesis. The results indicated that RVT-treated LNCaP cells introduced in S-phase then increasing growth of S-phase was hindered via obstruction of DNA synthesis by RVT specifically at dose >15 μm. Hence, RVT has special capability to employ antagonistic effects on two phenomena in cell cycle growth, i.e. hinderance of DNA synthesis and S-phase induction which might be the main factors behind the anti-proliferative and apoptotic effects (Rauf et al., 2018). The impact of two RVT’s stereoisomers on activity of ANO1 was examined. Moreover, trans- and cis-RVT hindered ANO1 activities with various potentials were also evaluated. Trans- and Cis-RVT prevented ANO1 channel activities with IC50 of 102 and 10.6 microM, respectively. The results suggested that the cis-RVT is a promising ANO1 inhibitor and depicted anti-cancer activities dependent on ANO1 against the metastatic PSC PC-3 cells of human (Jeon et al., 2023). RVT is a potent substance for metastasis-associated protein 1 (MTA1) directed anti-cancer and its anti-tumour effects for the treatment of PSC. MTA1, major transcriptional regulator and epigenetic reader and its linked microRNAs (miRNAs), plays a prominent role in all phases of PSC growth and metastasis. Moreover, MTA1-linked pro-oncogenic miRNAs identified in several studies were regulated by different stilbenes, i.e. RVT and pterostilbene. Particularly, the MTA1 inhibition activity modulated the oncogenic miR-34a, miR 22 and miR-17 (group of miRNAs) by RVT and Petro stilbenes causing the prostatic hyperplasia prevention and tumour growth in mice during in vivo study. Consequently, RVT and its derivatives can be used as miRNA-mediated therapeutic and chemo-preventive strategies in PSC and circulating miRNAs can be utilized as promising prognostic biomarkers for clinical developments (Levenson, 2022).

The combined effect of RVT and docetaxel (an anti-cancer medicine) on LNCaP cells of prostate carcinoma along with the factors linked to the comprehensive cell death phenomena. These depicted the synergistic inhibitory influences on cell progression, exhibited by an increment in sub-G0 / G1 peaks. ROS scavenger N-acetylcysteine was utilized for the pretreatment to rescue the necroptosis and apoptosis. The study suggested that RVT is a good adjuvant in DTX therapy to improve the PSC treatment (Lee & Lee, 2021). Cisplatin used during the treatment of ovarian, testicular and bladder as cancer chemotherapy agent. Its utilization is also linked with higher risks of nephrotoxicity. Various studies reported that RVT is capable to decrease cisplatin renal toxicity (Valentovic, 2018).

The impact of RVT inhibition on PSC induced by DHT metastasis was investigated. DHT enhanced the LNCaP PSC cells viability in cell viability assay. In contrast, the RVT along with bicalutamide (AMD3100 or AR-antagonist) as a CXCR4 preventer remarkably decreased the cell viability that was enhanced by DHT. Hence, RVT along with CXCR4 or AR antagonists might be helpful to reduce the metastatic manners of PSC (Jang et al., 2019). The resveratrol anti-proliferative effects in the regulation of expression of NF-kappaB and suppression of growth by the RVT-mediated directing protein (NQO2) using CWR22Rv1 cells silenced by NQO2 siRNA and control cells. The study claimed that the RVT-mediated directing protein (NQO2) significantly induced changes in NF-kappaB p65, resulting in anti-CaP functions caused by resveratrol (Hsieh, 2009).

4.5. Liver cancer

Liver cancer (LC) comes at 5th (548,000 cases/year; 6.3% among cancers) and 9th (244,000 cases/year; 6.3% among cancers) number according to its global prevalence rate in males and females respectively. The basic LC is a malignant, produced inside the liver (El-Melegy et al., 2021). GLOBOCAN 2020 database reported 9.06 million new cases of LC and ∼8.30 million deaths due to LC. Its prevalence and mortality are almost the same as it is diagnosed at the last stage in patients where the drugs therapy is the only one strategy to combat it. Many patients cannot obey the therapy treatments because of multidrug resistance development and drug-linked toxicities (Baby et al., 2021). Although, there are various types of LC but hepatoma or hepatocellular carcinoma (HCC) is the major type of LC and it initiates in the hepatocytes (major cells of liver). The HCC rate is very high and it is considered 4th most mortal cancer globally. The symptoms of LC appear with the increase in cancerous cell growth and include tiredness, weakness, abdominal pain, abdominal swelling because of excess of fluid (ascites), right shoulder pain, sickness and loss of appetite. Trans-resveratrol (T-RVT) has potential anti-cancer activities against hepatoma. T-RVT-loaded nanochleates were formed utilizing simple trapping methods and were investigated for their capability to suppress the expression of NANOG that lowers 2-folds in comparison to free T-RVT. These T-RVT-loaded nonchelated provide the potential nano-platform to increase T-RVT oral permeability and enhanced its anti-cancer properties in HCC treatment (El-Melegy et al., 2021).

Oxyresveratrol (ORVT), restructured RVT, was utilized to disclose its perspectives and molecular mechanisms for the treatment of LC via experimental validation and bioinformatics investigation. Purposely, molecular docking technology and pharmacology approaches were used to exhume the impact of ORVT on liver-anti-cancer targets, i.e. EGFR and estrogen receptor 1 (ESR1). The bioinformatics and authenticated findings have depicted the comprehensive molecular mechanisms and pharmacological targets in LC treatment. Similarly, experimental verification recognized the ESR1 gene. EGFR is a promising marker for anti-LC (Zhao et al., 2021). Huh7 and HepG2 cells were reacted with various RVT concentrations to study RVT molecular mechanisms in inhibition of LC metastasis and CCK-8 assay was utilized to observe the cell viability. RVT prevented the LC cell invasion and wound healing, enhanced the E-cadherin expression and reduced the expressions of Twist1 and vimentin. RVT up-regulated the miR-186-5p expression in LC tissues and prevented the LC metastasis (Song et al., 2021). RVT increased the ROS production to increase the tumour-suppressing gene DLC-1 expressions and DLC-1 prevented the DYRK1A-EGFR axis to stimulate the DNA damages occurred by upregulation of γH2AX (DNA double helical breaking marker protein) and dysregulation of DNA repairing linked proteins RAD51 and p-BRCA1, ultimately resulting in death of cancerous cell. It also effectively hindered the size of the transplanted tumour with enhanced SA-β-gal activities and DLC1 levels in chicken embryo xenograftic malignant model (Ma et al., 2023). RVT and dihydroartemisinin (DHA) in combined form synergistically hindered the relocation, decreased wound cessations and development of F-actin in MDA-MB-231 and HepG2 cancer cells. This mixture downregulated the expressions TCTP and up-regulated the malignant suppressing genes deleted in LC (DLC1). Consequently, RVT and DHA prevented the proliferation by regulating the DLC1/TCTP axis to inhibit the Cdc42-linked signalling pathways (Gao et al., 2020).

A unique heat-sensitive hydrogel drug system for targeted treatment of hepatocellular carcinoma (HCC) ascites via intraperitoneal management was developed. The mixture of cisplatin (DDP) and RVT was developed in heat-sensitive hydrogel (Pluronic F127). It was concluded that the F127 hydrogel drug significantly reduced the HCC, tumour cell migration, micro-angiogenesis and increased the survival rate of mice via intraperitoneal administration chemotherapy. This system was proved safe and less toxic by immunohistochemical staining (Wen et al., 2020). The promising impact of RVT on choline /methionine scarce diet induced NASH rat model was studied. RVT modulates the SIGIRR expression levels in rat liver. It dysregulated the expressions of inflammatory influences in liver and suggested that the proper consumption of RVT can inhibit the formation and incidence of NASH (Che et al., 2020). RVT can be used to alleviate hepato-carcinomas in response to metastasis however phytochemical berberine (BER) and RVT in combination are capable to cause cell death. The alterations in pleiotropic enzyme trans-glutaminase-2 (TGM2) activities were used to examine the effects of RSV/BER cotreatment on hepatocarcinomatous which resulted that their cotreatment can be beneficial in LC cancer chemotherapy (D'arcy et al., 2021). RVT therapy enhanced expressions of ZFP36 and reduced the levels of messenger RNA of ZFP36 targeted genes in LC cells (A549). RVT suppressed the DNA ([cytosine-5]-methyl-transferase-1) expressions and activated the demethylation of ZFP36 enhancer. Consequently, RVT depicted its anti-LC activities via epigenetic regulations of ZFP36 (Fudhaili et al., 2019). RVT maintained the lactate dehydrogenase, lactate, lipid peroxidation and urea levels which were enhanced during HCC. It also dysregulated the enhanced sirtuin-1 expression in HCC kidney. RVT also improved the oxidative stress in kidney of HCC-induced rats which was independent of glutathione peroxidase and dependent to catalase (Rawat et al., 2020). Resveratrol-loaded nano-gold particles (RVT-GNPs) were synthesized and characterized by transmission electron microscope (TEM), and zetasizer UV-Prove. The anti-cancer characteristics of RVT-GNPs were evaluated by western blot analysis, immunohistochemistry, TUNEL, flow cytometry and MTT assay in LC cells and tumour xenografts. The RVT-GNPs depicted better anti-cancer effects as compared to the simple RVT in vivo and in vitro study that might be due to GNPs that can deliver more RVT in the cells of mitochondria (Zhang, Yang, et al., 2019).

4.6. Lung cancer

LUC occurs in lungs, which are two spongy organs located in chest that inhale oxygen and exhale CO₂. LUC is considered as major reason of cancer deaths globally. The smokers are at front of risks of LUC but the cancer can also be prevailing in nonsmokers. The LUC risks upsurge with the increase in cigarette numbers and smoking duration. Nanotechnology strategies have been widely used to obtain the controlled release, enhanced solubility, higher stability and maximized oral bioavailability of RVT. The RVT-NPs have significantly increased its anti-cancer attributes to combat various cancers (Annaji et al., 2021).

Systematic researches depicted that resveratrol is capable to stimulate the tumour cell autophagy and apoptosis, hinder angiogenesis and cell cycles, modulate cyclooxygenase signal transduction pathways and nuclear factors, and prevent metabolic initiation of carcinogens and variate tumour-linked patterns of expressions, i.e. apoptosis, metastasis and malignant cell proliferation by antioxidation effects (Xin et al., 2023). RVT depicted dose-dependent anti-cancer effects by preventing cell propagation and encouraging cell apoptosis in NSCLC cells. It enhanced the LC3 II/I and Beclin1linked expressions and reduced the expression of p62, indicating the induction of autophagy in NSCLC cells by RVT. It activated the p38-MAPK pathway and inhibited the Akt/mTOR to induce autophagy and apoptosis and inhibit proliferation. RVT-induced autophagy can act as a protective mechanism to enhance the survival rate of NSCLC cell that leads to increment of anti-cancer attributes of RVT (Wang et al., 2018). Anoctamin1 (ANO1) is a calcium-started chloride channel that involved in invasion, migration and proliferation of cancerous cells such as prostate, lung, head and neck cancers. Cis- and T-RVT considerably decreased the cell migration and proliferation according to ANO-1 concentrations. RVT isomer significantly increased the apoptotic sub-G1 phase ratio, cleavage of PARP and caspase-3 activities in PC-3 cells. Cis-RVT is a promising preventer of ANO1 and exhumes ANO1 dose-dependent anti-cancer activities (Jeon et al., 2023). RVT enhanced the anti-cancer effects of gemcitabine (GEM) against LUC cells both in vivo and in vitro. The adenocarcinoma HCC827 xenograft of human lung was developed in nude mices and treated with RVT and GEM mixture to observe their synergistic impact in vivo model. RVT suppressed the endoglin expressions and enhanced the blood profusion and micro vessel progression tumour cells during LUC. However, the suppression of tumour growth by cotreatment of GEM and RVT was higher in comparison to GEM alone (Qin et al., 2020).

The resveratrol has a significant impact on enzymes linked with the accretion of two sphingolipids with maximum activities, i.e. proliferation-persuading sphingosine 1 phosphate (S1P) and apoptosis promoting ceramide (CER) in human lungs adenocarcinoma cells (A549). RVT significantly decreases the S1P and sphingomyelin (SM) and stimulates an increment in Sphingosine (SPH) and CER. Both expression and activity of CER synthase were up-regulated in RVT-treated cells, suggesting that stimulation of de novo synthesis is the reason for CER accumulation. Moreover, alkaline ceramidase (CER hydrolysis enzyme) was remained constant, implying that it is not linked with CER level variations. Sphingosine kinase 1 (SK1) enzyme responsible for proliferation and apoptosis was dysregulated and its S1P levels in lung adenocarcinoma cells treated with RVT (Momchilova et al., 2022). The impact of RVT derivatives (RVT-Ds) on cell propagation was examined by colony formation assay, nucleus staining and 2,5-diphenyl 2H-tetrazolium bromide (MTT) assay. The RVT-D2 (4,4'-(ethane-1,2-diyl) bis-(2-methoxyphenol)) hindered the cell propagation and induced apoptosis in comparison to control. RVT-D2-treated cells exhumed that the apoptotic nuclei linked with the decline in cellular p-mTOR and p-Akt. The stronger interaction between Akt molecules and RVT-D2 at allosteric and ATP binding sites was noticed in molecular docking analysis suggesting RVT-D2 is a promising Akt preventer. It was suggested that RVT-D2 is a potent agent to treat the LUC through inhibition of Akt/mTOR (Innets et al., 2022). The lncRNA MIR4435-2 host gene (MIR4435-2HG) is present on 2q13 chromosome of human and involved in 18 cancers via its up-regulated expressions. It takes part in mechanisms of three anti-cancer medicines, of which two are linked with LUC, i.e. RVT for LUC and cisplatin for nonsmall cells LUC (NSC-LUC) (Zhong et al., 2022).

The chemotherapeutic influence of polydatin (RVT natural analogue) and polydatin linked mechanisms in in vitro utilizing the LUC A549 cells was examined. A number of parameters i.e. wound healing, apoptosis, DNA damage, colony formations and MTT were used to evaluate the metastasis and cell propagation. The result indicated that polydatin is capable to induce the apoptosis and senescence in LUC A549 cells depending on concentration levels and regulation of polydatin by mTOR pathway is used to induce the differential bystander influences (Verma & Tiku, 2022). The anti-cancer mechanism of RVT was investigated on small-cell LUC (SCLUC) cell line H446. The treatment of RVT (40 µg/mL) was given to the cells with or without pretreating them with N-acetyl-L-cysteine (antioxidant). Flow cytometry and MTT were used to analyse the H446 cell apoptosis and viability and the western pathway was used to examine the apoptosis nuclear translocation introducing factor, PI3 K/Akt/c-Myc pathway and cytochrome c expression. The results revealed that RVT can enhance the apoptosis and prevent the cell viability of H446 SCLUC of human cells via PI3 K/Akt/c-Myc pathway and aforementioned phenomena may include the involvement of potential depolarization of mitochondrial membrane and oxidative stress (Li et al., 2020). RVT time and dose dependently decreased the cell viability. It increased the H446 cell hindrance by cisplatin as suggested by enhanced apoptosis and decreased cell viability. Intrinsic apoptosis regulation helped RVT for enhanced the H446 cell killing by cisplatin (Li et al., 2018). The inhalable therapy was developed to increase the stability and solubility of RVT by combining it with sulfo-butyl-ether β-cyclodextrin (SBECD) in LUC respiratory model disorder. Cell viability in 5 NSC-LUC cell lines suggested that RVT-SBECD reserved the considerable cytotoxic capability of RVT. Consequently, RVT-SBECD was proved a potent inhalation therapy for NSCLUC (Wang et al., 2020).

4.7. Kidney cancer

The 13th most prevalent cause of cancer mortality globally, renal cell carcinoma (RCC), often known as kidney cancer, is the 6th and 10th most frequent malignancy in both men and women, causing over 140,000 deaths annually (Ferlay et al., 2015; Siegel et al., 2018). According to a review of the SEER database, between 2006 and 2015, RCC prevalence increased by an average of 0.6% year but mortality rates decreased by an average of 0.7% annually. With an average age of 64 years at diagnosis, RCC accounts for around 3.8% of the total number of new cases of cancer (Seer, 2019). RCC makes up over 85% of kidney tumours, and about 70% of them have ccRCC (clear cell histology) (Lipworth et al., 2016). Translocation, chromophobe, Bellini duct (collecting duct), papillary tumours are other less prevalent cell types. 90% of all cases of cancer of the kidneys in adults are RCC, which develops in the inner layer of the distal convoluted tubule (Nabi et al., 2018). According to Msaouel et al. (2019), medullary renal carcinoma is an uncommon and severe RCC variation that exclusively affects those who have the sickle-cell characteristic. Anaemia, elevated blood pressure and reduced kidney filtration are characteristics of RCC and lead to renal failure (Capitanio et al., 2019).

Hypertension, obesity and smoking are considered to be the risk factors for RCC progression. RCC is not recommended to be screened for, but it is becoming more common. Additionally, epidemiological investigations link an upward trend in related risk factors such obesity and hypertension to an increase in RCC (Decastro & Mckiernan, 2008). There are a number of genetic RCC subtypes, the most prevalent of which is VHL (von Hippel-Lindau) disease. According to Schmidt and Linehan (2016), the VHL gene has an autosomal-dominant constitutional mutation that makes people more likely to develop ccRCC and other proliferative vascular diseases. According to Barata and Rini (2017), current RCC treatment options include chemotherapy, nephrectomy, radiation and immunotherapy. Changes in lifestyle have been demonstrated to increase cancer-specific longevity and lower the incidence of a number of malignancies (Stein & Colditz, 2004). As a result, lifestyle modifications may have an impact on results and can be a low-cost preventive and supplementary programme that is customized for each patient. When it comes to natural goods and phytochemicals, resveratrol is well known for its ability to fight cancer. Various studies have found that resveratrol therapy is effective in treating RCC or kidney cancer.

In an investigation conducted in 2018, Kabel and colleagues looked at the effects of resveratrol or its combination with sitagliptin on a mice model of experimental renal cancer. A dipeptidyl peptidase-4 (DPP-4) inhibitor called sitagliptin is used for the treatment of diabetes type 2. The drug has lethal effects on tumour cells via inhibiting autophagy, which suggests that it might be a novel chemotherapy regimen. This research demonstrates resveratrol and sitagliptin's developed synergistic effect in their anti-inflammatory and antioxidant capacities through their modulatory impact on STAT3/NF-B and Nrf2/HO-1 signalling. These substances enhanced ccRCC and kidney function. In treated ccRCC, sitagliptin reduced ROS and resveratrol resulted in a significant increase in the expression of the antioxidant enzymes. The synergistic effect of resveratrol and sitagliptin could be a significant therapy for the treatment of ccRCC (Aires et al., 2014). In a recent study, the therapeutic effect of resveratrol was studied on arsenic-exposed mice models having bioaccumulation of arsenic in liver and kidneys concluding the fact that, resveratrol remarkably ameliorated the renal and hepatic toxicity in effected mice models because of its potentially strong antioxidant effect (Irshad et al., 2021). In another study, during aflatoxin-B1-induced hepatocellular carcinoma (HCC), the role of nicotinamide and resveratrol in renal failure was investigated. The findings revealed that resveratrol therapy normalized the levels of lipid peroxidation, lactate and lactate dehydrogenase and urea which were elevated in HCC. Further, regulation of oxidative stress in kidneys of mice having HCC through resveratrol was observed to be dependent on catalase and independent from glutathione peroxidase (Rawat et al., 2020).

ACHN cells of nude mice were administrated with resveratrol for 40 days. The resveratrol treatment markedly decreased the tumour weight and volume on 40th day. 60% of mice survived in the control group on day 40 whereas, all the mice survived throughout the experiment in resveratrol-treated group. Moreover, resveratrol significantly decreased the cancer cells proliferation, invasion and migration and also induced apoptosis in RCC (Tian et al., 2020). The migration and invasion capacity of RCC cells and its mechanisms were studied after using a combination of resveratrol nanoparticle and U0126. The results showed a significant suppression and decrease in migration and invasion of RCC cells via inhibiting the ERK (signal-regulated kinase) signalling and matrix metalloproteinase-2 (MMP-2) expression (Zhu et al., 2022). According to recent research, resveratrol may enhance its ability to limit tumour growth by altering the signalling pathways of cellular agents (T cells, macrophages and fibroblasts). Additionally, research has demonstrated that resveratrol possesses the ability to inhibit the malignant traits that tumour cells might develop in reaction to stressors in the microenvironment of the tumour, such as oxidative stress, inflammation and hypoxia (Han et al., 2019).

RCC cells might be made more susceptible to TRAIL-induced demise in vitro by resveratrol tumour necrotic factor-related apoptosis-inducing ligand (TRAIL) combination therapy, according to a recent research by Zeng et al. (2020). The RCC implant growth was significantly inhibited when a combination treatment was given to nude mice. When resveratrol and arsenic trioxide (ATO) were combined, the latter's ability to induce apoptosis in Adriamycin-resistant leukaemia K562/RA cells was enhanced. Resveratrol also lessened the harmful effects of ATO alone.

4.8. Breast cancer

Breast cells growth becomes uncontrollable and they proliferate rapidly, this condition is referred as breast cancer. The development of breast cancer occurs in several forms. The form of breast cancer is dependent on the type of cell which proliferates and becomes the cause of cancer. Breast cancer may emerge from different regions of breast. The basic components of breast include these three: lobules, ducts and connective tissues. Milk generating gland is actually lobules and from there the milk flow through small tubes which are ducts towards the nipple. Fatty and fibrous tissues collectively make the connective tissues that hold and envelop everything in place. The region where mostly the breast cancer starts is ducts or lobules. Among different techniques and therapies, resveratrol proved its anti-cancer and anti-neoplasmic role against breast cancer in different studies. ATP2A2 and ATP2A3 gene expression levels were evaluated in cell lines of different types of breast cancers. The results showed that MCF-7 cell line represents a greater expression of ATP2A3 than the MDA-MB-231 cell line. The use of natural compound resveratrol induces apoptosis, reduces proliferation of cancer cells and also induces the expression of ATP2A3 in both cell lines (Zarain-Herzberg et al., 2021).

Due to its high affinity for Erβ and Erα (estrogen receptors) and concentration-based estrogenic and anti-estrogenic ability resveratrol has shown its capability against breast cancer. If cytostatic agents were used synergistically with polyphenols then an enhanced anti-cancerous effect can be obtained. Moreover, its anti-inflammatory properties will also help to protect the healthy cells from the aggressive nature of anti-tumour drugs (Vladu et al., 2022). One of the fatal types of breast cancer is TNBC (triple-negative breast cancer). For the survival rates to be increased, alternative approaches for its treatment should be investigated. For this purpose, a research was conducted to study the cytotoxic effects of non-prenylated resveratrol and prenylated stilbenoids arachidins A-1 and A-3 on TNBC cells of human. These were used as capable adjuvants for paclitaxel (Pac). The results figured out the inhibited growth of TNBC spheroid, obstructed the cells in M-phase, reduced cell proliferation and induced apoptotic cell death and activation of p53 expression. The combination of Pac and A-1 showed greater results than the other combinations (Mohammadhosseinpour et al., 2023). The effect of free resveratrol and curcumin in comparison to encapsulated resveratrol and curcumin in milk-derived exosomes (EXOs) on cell lines of breast cancer was studied by González-Sarrías et al. (2022). MDA-MB-231, MCF-7 and MCF-10A cells were used for analysing the anti-proliferative effects of EXO-Resveratrol and EXO-Curcumin. The outcomes demonstrated that the anti-cancer effect and bioavailability of resveratrol and curcumin were enhanced by milk-derived EXOs. Jiang, Yu, et al. (2022), investigated the anti-tumour effect of tripolyphosphate-resveratrol (TPP-resveratrol) in MDA-MB-231 cell lines of human breast cancer and 4T1 cells of murine breast cancer. The potential loss of mitochondrial membranes, cell cycle inhibition and induction of apoptosis was studied using flow cytometry. There was a potential improvement in cytotoxity of MDA-MB-231 and 4T1 cells via inducing apoptosis and potential loss of mitochondrial membranes.

4.9. Ovarian cancer

OC is the 8th most prevalent cause of cancer-related mortality in women worldwide and the 7th most common cancer overall (Zhang, Zhang, et al., 2019). According to estimates, OC kills around 100,000 women per year in the world (Xia et al., 2021). Additionally, according to Gaona-Luviano et al. (2020), OC is the main factor in deaths from female reproductive tract cancer globally. Although the root cause of OC has not yet been fully explained, it has been shown that potential risk factors for OC include obesity, genetic conditions, advancing age, alcohol use, diabetes mellitus and smoking (Henley et al., 2020; Reid et al., 2017). It is stated that ovulation, hormonal and environmental variables may play a part in the etiology of OC (Gong et al., 2020). Galactose metabolism, which is connected to the risk of OC development, is one of the routes that has been reported to be associated with OC progression (Wang et al., 2020). Since the reported indications in the initial phases of the condition are not clearly associated with OC, that is why OC is frequently referred to as the “silent killer” (Patra et al., 2010). Abdominal discomfort, unusual bowel patterns and sudden satiety are only a few examples of the widespread and perplexing symptoms of OC (Gatti et al., 2021). Stromal cells, germ cells and surface epithelium are three main cell types that give rise to cancerous ovarian tumours. Epithelial OC (EOC), a chronic heterogenic condition and the most prevalent kind of OC, can be visually separated into four subtypes, i.e. clear cell carcinomas, serous, endometrioid and mucinous (Oliveira et al., 2021). More than 95% of ovarian malignancies are EOC-related. Furthermore, a large proportion of patients with EOC tend to acquire chemoresistance in later stages (Corradetti et al., 2019; Kanlikilicer et al., 2018). The RVT effects on different ovarian cell lines for the treatment of OC are given in Table 2.

Table 2. Utilization of resveratrol formulations in various ovary cell lines to cure OC.

Resveratrol formulations	Cell lines / animal models	Mechanism	Main anti-cancer effect	References
Resveratrol	OVCAR-3 and OC-CAOV-3	Increase ARHI; Apoptosis; decrease the metastasis induced by IL-6; p-STAT3	Enhanced autophagy, less proliferation activities	(Zhong et al., 2018)
Resveratrol	A2780	Decrease p-ErbB3; p-EGFR; increase ROS; lower p-ErbB2	Inhibited cell migration, proliferation. Prevented development of cisplatin resistance	(Engelke et al., 2016)
Resveratrol	NIH-OVCAR3	Increase p-eIF2α; decrease mTORC1; improve p-AMPK; decrease p-AKT; p-4EBP1	Initiated autophagy, stops protein synthesis and cell growth	(Ferraresi, Phadngam et al., 2017)
Resveratrol	NIH-OVCAR3 Inhibited cell migration ↑ARHI; ↓p-STAT3; ↑Beclin-1; ↓p-AKT;	Increase Beclin-1; ARHI; decrease p-AKT; p-STAT3	Suppress cell migration	(Ferraresi, Titone et al., 2017)
ADR+ curcumin + micellar resveratrol; Quercetin + Micellar resveratrol + ADR	ES2-Luc xenograft model	Chemo sensitization	Reduced tumour volume	(Al Fatease et al., 2019)
Acetyl-resveratrol + resveratrol	SKOV-3	Decrease NF-κB; VEGF; increase IL-8	Reduced cell growth	(Tino et al., 2016)
Resveratrol	C57BL/C mice were inoculated with ID8 cells	Increase IFN-γ; decrease TGF-β	Lowered tumour volume	(Zhang, Zhang et al., 2019)
Resveratrol	SKOV-3, OV-90, miR-34a	-	Induced apoptosis, inhibited migration and invasion of cells. Reduced cell proliferation, overexpression of miR-34a increases the anti-cancer effect of resveratrol	(Yao et al., 2021)
Arginylglycylaspartic acid (RGD) conjugated resveratrol human (HAS) nanoparticles	SKOV-3	Decrease expression of αvβ3 integrin	Greater cellular inhibition and cellular uptake rates, increases the anti-cancer effect	(Long et al., 2020)
Resveratrol + arsenic trioxide	A549	Increase BiP; CHOP; caspase-12, ER stress signalling	Induced apoptosis, increased anti-cancer effect	(Gu et al., 2016)
Resveratrol	MDAH2774; Pa-1; SKOV3	Increase PERK; CHOP; IRE 1α; ATF6α; BiP, ER stress signalling	Induced cellular apoptosis, activation of ER-stress sensors	(Gwak et al., 2016)
Micronized trans-resveratrol	34 patients		Lowered total testosterone, fasting insulin levels and enhanced index of insulin sensitivity	(Banaszewska et al., 2016)

The procedures used in today's cancer therapies include chemotherapy, surgery, immunological therapy and radiation. Nevertheless, because of treatment resistance and unintended side effects, the death rate is still significant (Siegel et al., 2018). However, chronic chemotherapy administration might result in chemoresistance and undesirable side effects. Thus, it is critical to find new treatment drugs based on our knowledge of the molecular processes involved in the development of OC. Natural compounds produced from plants are being studied as substitutes or additional therapies for a range of cancer types due to the substantial toxicities associated with traditional anti-cancer medications (De et al., 2013). Recent research has shown the anti-cancer properties of organic substances and that they may lessen the toxicity brought on by chemotherapy. Numerous phytochemically derived metabolites and their extracts have been investigated in relation to ER stress in OC. Several compounds have demonstrated inhibitory activity against ER stress, including resveratrol, curcumin, quercetin, fucoidan, fucosterol, epicatechin gallate and cleistopholine (Singla et al., 2022). Resveratrol, quercetin, ginsenoside, berberine, curcumin and EGCG are the main phytochemicals in this group (Hosein Farzaei et al., 2016). However, recently, nano-based drug delivery methods have been created for the treatment of OC, including nanoparticles (NPs), liposomes, nano micelles, branching dendrimers, nanocapsules and nanostructured lipid formulations (Barani et al., 2021). Therefore, combining herbal therapy with nanotechnology-based therapy may open up new possibilities for the treatment of OC.

According to a study conducted by Seino and colleagues, resveratrol successfully kills ovarian CSCs (cancer stem cells) without the need for ROS, however CSCs that were resistant to resveratrol therapy were decreased by ROS (Seino et al., 2015). RVT suppresses EMT induced by cisplatin, which is fundamental step in cancer development (Baribeau et al., 2014). RVT also inhibits the growth of insulin-stimulated serum-starved PA-1 cells, activates caspase-9, caspase-7 and caspase 3, and causes apoptotic cell death in PA-1 cells. The development of human OC PA-1 cells was the subject of an investigation by Lee and colleagues. They discovered that RVT suppresses serum- or insulin-induced proliferation of OC PA-1 cells by reducing the expressions of eEF1A (Lee et al., 2009). Resveratrol also greatly reduces the amount of mTOR and phosphorylated Akt as well as glucose absorption, lactate generation, and EOC cells production of lactate (Kueck et al., 2007). Resveratrol's anti-cancer properties were brought on by its suppression of STAT3 signalling (Zhong et al., 2015). In resveratrol-induced apoptotic cell death in human OC cells CAOV-3 and OVCAR-3, the significance of autophagy was also discovered. According to Lang et al. (2015), resveratrol triggers the production of ROS, which leads to autophagy and apoptotic death. mTOR/AKT/P13 K pathway activation is related to proliferation as well as survival of EOC cells. This pathway also causes greater migratory capacities and attacking capability of ovarian tumour cells. So, its inhibition can be a strategy to reduce cancer. For this purpose, resveratrol in combination with curcumin was used in a study by Muhanmode et al. (2022) in addition to cisplatin treatment for the inhibition of P13 K pathway to reduce OC. The synergistic effect of resveratrol and curcumin drastically inhibits the mTOR/AKT/P13 K pathway hence reducing OC. Resveratrol anti-proliferative effect against ovarian tumour cells was studied via CCK-8 assay and concluded that treatment of resveratrol reduces proliferation, introduces apoptotic cell death and stops the migration and invasion of OC cells SKOV-3 AND OV-90 (Yao et al., 2021). By recovering glycolysis-mediated suppression of autophagy, RVT can halt the growth of IL-6-induced ovarian tumour and lend credence to the idea that focusing on Warburg metabolism might reduce the likelihood of cancer spread (Vidoni et al., 2023). By eliminating dyslipidemia, lowering insulin resistance, enhancing anthropometric indices and ovarian morphology, managing the reproductive hormones and decreasing oxidative stress as well as inflammation by influencing biological pathways, the administration of resveratrol may be effective in relieving PCOS-related ailments (Karimi et al., 2022). According to a study conducted by Liang et al. (2023) different concentrations of resveratrol were given to ovarian granulosa cells collected from infertile women under the age of 35 having poor ovarian responder (POR), polycystic ovary syndrome (PCOS) and endometriosis and analysed cellular apoptosis via flow cytometer method. This study concluded that apoptotic factor was affected by resveratrol treatment to protect the state of human ovaries.

4.10. Brain cancer

Brain cancer is abnormal growth of cells in brain. The brain anatomy is very complicated, consisting of various parts responsible for different functions of the nervous system. Brain cancer can be occurred in section of brain, i.e. the sinuses, brainstem, nasal cavity, protective lining, inside the brain/skull, etc. depending on tissues of brain, there are 120 kinds of brain tumours has been reported (Valvona et al., 2016). The miRNA is listed among one of the major substances in molecular micro-environments. These are noncoding small RNAs which play a key role in expression of genes, post transcriptionally. Brain tumour and neurodegeneration are supposed to affect the fundamental pathways of differentiation, cell propagations and cell senescence which are strictly modulated by miRNAs (Ghosh et al., 2021). Figure 4 depicts the mechanism of brain cancer development and impact of RVT in treatment of brain cancer by preventing the P-glycoproteins.

Figure 4. Mechanism of brain cancer development and role of resveratrol in its management.

The impact of RVT on doxorubicin-resistant glioblastoma cells (U87MG/DOX) and human U87MG survival was evaluated by MMT. RVT inhibited the growth of glioblastoma cells, up-regulated the PTEN to reverse the chemoresistance and suppressed P-glycoprotein and AKT (Zhang et al., 2023). The cytotoxicity assay (MAT) exhumed the similar effects of solid lipid nanoparticles (SLNPs) developed by combination of glyceryl behenate and RVT to the simple RVT as anti-cancer agents. The in vivo distributial trail on Albino Wister rats revealed that the RVT bioavailability of SLNPs was higher (17.28 ± 0.6344 μg/g) in comparison to the simple RVT (3.45 ± 0.3961 μg/g). Consequently, RVT-loaded SLNPs can provide a potent therapeutic system to cure the neoplastic disorders occurred in brain tissues (Jose et al., 2014).

4.11. Skin cancer

Skin cancer (SC) is considered as foetal type of cancer worldwide (Karimkhani et al., 2017; Ünver & Ayan, 2019). The prevalence rate of malignant melanoma and non-melanoma skin cancer has been increasing for last few years due to chronic effects of UV radiation (Reis et al., 2019). Various types of skin cancers, i.e. intraepithelial carcinoma, squamous cell carcinoma, basal cell carcinoma, melanoma and many others are prevailing globally. The human skin consists of three tissue layers generally known as epidermis, dermis and hypodermis. The former layer consists of melanocytes that might synthesis melanin in higher rates which considered abnormal in many situations, i.e. melanin produced due to exposure of skin to the strong UV radiation of sunlight. Melanoma is a foetal type of skin cancer produced due to abnormal growth of melanocytes (Siegel et al., 2019). The diagnosis of melanoma at the early stage in very necessary for its treatment and survival rate increased to 5 years in 92% patients at the early stage diagnosis. The visual assessment of benign and malign skin abrasions is the main issue in the identification of melanoma. It is very problematic to determine the lesion type via naked eyes (Adla et al., 2022).

The complex of RVT and lipid carrier gel of 5-fluorouracil nanostructures was prepared, improved and characterized to increase the permeability between dermis and epidermis layers of skin to attain the synergetic effects against skin cancer. The results depicted that lipid-nanosystem loaded with dual drugs result to the formation of steady formulations which also enhanced the retaining attributes of both RVT and 5-fluorouracil between dermis and epidermis layers of skin aiding in skin cancer therapy (Iqubal et al., 2021). RVT novel derivatives (1, 3, 5-triazine), extracted from RVT prototype were formulated and characterized. These compounds depicted the UV protection factors (UVPF) and sun protection factors (SPF) in the range of 3–13 and 3–17, respectively. These values were higher than ethylhexyl triazone (UV filters) and RVT currently present in markets. These derivatives exhibited the in vitro thermal stability at >236°C temperature and antioxidant activities, making them unique for skin cancer treatments (Reis et al., 2019). The combined effect of different phytochemicals, i.e. RVT, ursolic acid (UA) and calcium D-glucarate (CG) on early stages of skin cancer, i.e. initiation and propagation. The 7,12-dimethyl-benz[a] anthracene (DMBA)-stimulated and 12-O-tetradecanoylphorbol-13-acetate (TPA) propagated multistage skin tumourigenesis model was used in SENCAR mices. DMBA/TPA utilization enhanced the p50 and c-jun which were inhibited by various treatments. This treatment sturdily enhanced the mRNA concentrations of inflammatory markers, i.e. iL-6 and COX-2. The anti-propagation treatments resulted the significant reduction in IL-6 and COX-2 expression in comparison to DMBA/TPA control (Kowalczyk et al., 2013).

4.12. Blood cancer

It is a type of cancer occurs due to the abnormal growth of blood cells by mutations in their DNA sequences leading to create their abnormal functions. According to the Leukemia and Lymphoma Society (Society, 2017), 1,290,773 patients with blood cancer were reported in the United States. The general kinds of blood cancer are myelodysplastic syndromes, lymphoma, leukaemia and myeloma. To be separated, blood cancer affects the lymph nodes, bone marrow, blood cells and many other sections of lymphatic system. Various strategies are being developed to prepare better immune system that can be able to combat with cancer cells. RVT obstructed the Tax activity of LTR and HTLV-1 in SIRT1 deacetylase-dependent manners. It also activated the SIRT1 in HTLV-1-transformed T cells by inhibition of Tax expressions and proviral transcriptions. However, RVT compromised the SIRT1 via particular preventers that enhanced the expression of HTLV-1 mRNA. The finding depicted the negative regulatory action of SIRT1 in activation of tax linked with HTLV-1 transcription. Resveratrol could be considered advanced prophylactic in small molecules activation of SIRT1 and therapeutic substances in HTLV-1-linked disorders (Tang et al., 2015).

4.13. Colorectal cancer

It is type of cancer, in which the abnormal cell growth occurs in colon and rectum of the intestine. Rectum and colon are the parts of body of digestive system (DS). The DS collects different nutrients (water, protein, fats, carbohydrates, minerals and vitamins) from the ingested meals and excretes the waste materials from body through these parts. The DS is consisted of oesophagus, stomach, small intestine and large intestine. The colon is 5 ft long first part of large intestine (Laquerre, 2020) and the last part of large intestine is 6–8 in. long consisted of rectum and anal canal which ends at anus (Zhang et al., 2020). It was estimated that 153,020 persons will be diagnosed with CRC and 52,550 individuals will die due to CRC, of which 3750 deaths and 19,550 cases will be diagnosed in persons have age less than 50 years (Siegel et al., 2023).

The higher expression of pre-mRNA processing factor (PRPF) reduced the ROS intracellular levels, and prevented RVT-stimulated apoptosis by triggering the cell survival gesticulating proteins c-MYC, ERK and NFκB in human colon cancer cells (HCT116) was examined. The findings suggested that PRPF hindered the apoptotic effects through EMT induction, activation of cell survival signalling pathways and rearrangements of actin cytoskeleton. The illumination of these mechanisms which motivate the PEPF’s anti-apoptosis effects and resistance of anti-cancer drugs can provide the treatment basics to prevent the metastasis and tumour progression in different cancers (Islam et al., 2017).

The anti-cancer attributes of resveratrol in cancer stem-like cells (LoVo/DX) and colon cancer cells (LoVo cells) were studied. RVT depicted significant effects in cells of colon cancer which were expressing the higher sensitivity to drugs used for cancer in comparison to CSC-alike cells. It also played a key role in SIRT gene expression (Moreira et al., 2022). N, O-carboxy-methyl chitosan RVT-nanoparticles (CMCS-RVT-NPs) and N, O-carboxy-methyl chitosan Oxaliplatin nanoparticles (CMCS-OXE-NPs) were developed by emulsification crosslinking and ion crosslinking respectively. The aforementioned NPs depicted the markable anticolon cancer activities in compression to alone nanoparticles and free drugs, highlighting the potent of combined resveratrol and oxaliplatin Nps in drug delivery system in treatment of CRC cancer (Wang et al., 2021). The effect of RVT and RVT-NPs on vascularity and propagation of orthotopic and xenograft mice models in the CRC (COLO205-luc) was investigated. Both depicted considerable decline in haemoglobin levels and cancer propagation of cancerous part, but RVT-NPs exhibited higher efficacy and bioavailability than simple RVT (Sudha et al., 2020).

The effects of RVT on pyroptosis CRC were observed via in vivo and in vitro studies. The expressions of IL-18, Caspase-1 and NLRP3 proteins were enhanced considerably in vivo, and expressions of IL-18, NLRP3 and GSDMD-N proteins were enhanced remarkably in miR-31 mimic group and reduced significantly in miR-31 inhibitor groups. The behaviour of RVT in the above parameters depicted its inhibitory action in pyroptosis of CRC (Ren et al., 2022). The disturbance in interactions between TEAD and YAP and activation of Hippo/YAP signalling by RVT is a major reason behind its anti-cancer activity and suggested RVT a potent drug for CRC treatment (Qin et al., 2022). According to a study, the main reason behind the death of CRC patients is due to metastasis having epithelial–mesenchymal transition (EMT) as its major step. Oxyresveratrol (OXY-RVT), natural derived from RVT hinders human CRC cell movements by regulating miRNAs and EMT resulting that OXY-RVT increases the anti-metastatic attributes of CRC (Lin et al., 2021). The proliferated colon cancer cells were treated with p53 (Nutlin3a) and SIRT5 (Suramin and Resveratrol) modulators in separate or in combinations with 5-FU and impact of 5-FU on expressions of FOXO3a and SIRT5 proteins either with or without p53. The western bolt experiments suggested that the expressions of SIRT5 reduced by Suramin and expressions of FOXO3a protein reduced by RVT considerably in HCT-116 cells via p53 dependent manner, however, independent to p53, 5-FU reduced the expressions of FOXO3a and SIRT5 proteins suggesting their anti-cancer attributes (Ekremoglu & Koc, 2021). The RVT hindered proliferation activity and colonial propagation in HCT1 and DLD1 colon cancerous cells but did not damage the epithelial cells. RVT targeted the threonine kinase 1 and threonine kinase 2 to reduce the colon cancer cell and provide a promising chemotherapeutic treatment (Li et al., 2019).

5. Conclusion

Resveratrol is a potential substance of stilbenes family that can be utilized in treatment of number of diseases, the current review covered the various effects of resveratrol in treatment of a large number of cancers. Therefore, it can be concluded that it is a promising substance which can be utilized in pharmaceutics, therapeutics and medicinal sectors to gain its multiple benefits.

Disclosure statement

No potential conflict of interest was reported by the author(s).