Resveratrol and Urological Cancers: Taking Stock of the Current Evidence

Abstract

Urological cancers, such as prostate cancer (PC), bladder cancer (BC), renal cell carcinoma (RCC), and testicular cancer (TC), are major causes of morbidity and mortality. Effective therapies depend on factors such as cancer type, stage, grade, the individual's overall health, and treatment priority. Currently, treatment options include surgery, radiation therapy, targeted therapy, chemotherapy, and immunotherapy, but these approaches often face challenges including treatment resistance, disease recurrence, cytotoxicity, and severe complications. Natural products have emerged as promising sources for new drug development, and resveratrol, a natural polyphenolic compound found in berries, nuts, red wine, and grapes, has garnered significant interest. Resveratrol exhibits a range of biological effects such as anti-inflammatory, antiviral, antioxidative, antiproliferative, and anti-angiogenic activities. Results of this study highlights evidence that resveratrol can inhibit tumor cell proliferation, induce apoptosis, and suppress metastasis in various urological cancers. Moreover, it modulates key molecular pathways implicated in cancer progression, including PI3K/Akt, NF-κB, and STAT3 signaling. These findings suggest that resveratrol holds potential as an adjunctive therapeutic agent for urological cancers, though further clinical studies are warranted to confirm its efficacy and optimize its clinical application. This literature review has been performed to discuss the possible anticancer effects and mechanisms of resveratrol in relation to urological cancers, with a focus on PC, BC, RCC, and TC.

Introduction

Urological system-related health problems have become progressively common around the world and influence subjects in a broad range of ages.^1,2 Urological cancers, like prostate cancer (PC), bladder cancer (BC), renal cell carcinoma (RCC), and testicular cancer (TC), are associated with increasing morbidity and mortality rates per year. ³ In 2021, over 400,000 newly identified cancer cases and over 66,000 cancer-related death cases were attributed to urological malignancies in the United States. ⁴ Some factors increase the risk of occurrence of this type of cancer, for instance, chronic irritation, exposure to chemical and environmental (particularly cigarette smoking), aging (especially subjects in the range of 50-70 years), and genetic deviations, for instance, dysregulation of TP53, TP63, RB1, EGFR genes and Ras and p21 proteins. ⁵ The standard therapeutic approaches for urological cancers are determined by multiple factors, including type, stage, grade of cancer, individual's overall health status, and treatment priority. Conventional therapies for these urological neoplasms comprise surgery, radiation therapy, targeted therapy, chemotherapy, and immunotherapy.^6–8 Unfortunately, these therapeutic methods face some challenges, such as the risk of treatment resistance and disease recurrence, cytotoxicity, and incidence of rigorous complications. ⁹ Finding and harnessing novel therapeutic strategies is important for urological cancers. ⁵ One of the key sources in drug design and development is natural compounds. ¹⁰ For decades, humans have recognized natural herbal formulations for maintaining health, preventing diseases, and supporting physical and mental health. The increasing usage of natural compounds originates from their high acceptability, better safety profile with fewer side effects, effective multi-faceted biological actions, and economic affordability. The sum of these characteristics make natural compounds promising alternatives in medicine, cosmetics, and food industries.^11,12 In this regard, resveratrol (35,4′-trihydroxy-trans-stilbene), a polyphenolic compound found in various foods including berries, nuts, wine, and grapes, has demonstrated significant potential to improve a wide range of conditions such as cardiovascular diseases, neurological disorders, diabetes, infertility, and more.^13–16 This compound has also been found to exert diverse biological and pharmacological beneficial influences, such as anti-inflammatory, antiviral, and antioxidative, as well as anticancer, antiproliferative, and anti-angiogenic activities in different cancers. ¹⁷ From a molecular viewpoint, the structure of resveratrol consists of two phenolic rings with para-hydroxyl and ortho double hydroxyl groups linked by a double bond. ¹¹ In recent years, several documents accentuated urological cancer therapy by this natural compound through various molecular and cellular mechanisms.^17–19 Hence, this literature review aims to recapitulate evidence regarding the anticancer potential of resveratrol for improving urological cancers with a mechanistic focus.

Search Strategy

In this narrative review, related documents with the status of “In press” and “Published” in the English language have been evaluated qualitatively. The inclusion criteria were papers (original and review articles) focusing on the functionality of resveratrol in urological cancers, comprising prostate cancer, bladder cancer, renal cell carcinoma, and testicular cancer, preclinically (in vitro and in vivo) or clinically. Papers that lacked relevance to the purpose of the study, not peer-reviewed, or provided inadequate information were excluded. The used keywords include “Resveratrol,” “Prostate cancer,” “Bladder cancer,” “Renal cell carcinoma,” and “Testicular cancer” in different databases like Google Scholar, Scopus, PubMed, Web of Science, and Scientific Information Databases from 2007 until 1 March 2025.

Resveratrol and Prostate Cancer

PC is ranked the second most common malignancy and the fifth underlying reason for cancer-related death in men populations globally. ²⁰ In the United States, 268,490 newly identified subjects with PC and 34,500 death cases as a result of this disease were reported in 2022.^21,22 Using standard therapies for patients with PC is along with several challenges, like resistance to treatment and side effects. So, there is an indispensable need for finding alternative methods to solve these problems. ²³ Several papers have reported the potential role of natural polyphenols, including resveratrol (Table 1), in treating prostate neoplasms in experimental investigations.^24–27 As an example, in the study of Wang et al, the anti-PC effects of resveratrol at different concentrations were investigated in vitro and in vivo. The in vitro assessment was performed by exposing PC cell lines (LNCaP cells) to a medium comprising FBS (10%) with different doses of resveratrol (0, 1, 5, and 25 μM). The reports of RT–PCR and Microarray analyses showed the downregulation of kallikrein 3 (PSA), upregulation of BCHE (downregulated by androgen), stimulation of CDKN1A, as a cyclin suppressor orchestrated by p53, as well as the attenuation of expression of FRAP1–mTOR and IGF-1R mRNAs (androgen-associated mRNAs). Also, the in vivo results of this work revealed that this phytochemical (50 and 100 mg diet) could suppress cancer cell growth in a nude mouse xenograft model of LNCaP cells probably by regulating both estrogen and androgen-related occurrences. ²⁸ Another preclinical project studied the function of resveratrol as a radiosensitizer agent by affecting cancer stem cells in PC cells, PC-3, resistance to radiation therapy by tracing the markers of EMT (E-cadherin and Vimentin) and stem cells (DCLK1, CXCR4, OCT4, SOX2, CD29, CD49b, and CD44). ²⁹ Cancer stem cells are a small population of cells in tumors with the ability of self-renovation and differentiation into diverse lineages that theoretically construct the foundation of tumor development, metastasis, and therapy resistance. ³⁰ The results of the mentioned research team suggested that resveratrol administration could reduce cancer cell survival and abate stem cell and EMT markers at different doses (35-140 µM) in vitro. ²⁹ Other experimental investigations have suggested resveratrol in PC therapy in light of its various cellular and molecular therapeutic mechanisms, such as inhibiting angiogenesis by attenuating vascular endothelial growth factor (VEGF), decreasing or suppressing the levels of matrix metalloproteinases (MMPs) and tumor necrosis factor receptor-associated factor 6 (TRAF6) and hedgehog (HH) signals, suppressing the Akt radio-resistance pathway, boosting the tumor suppressor AMPK, downregulating oncogenic microRNAs (the clusters of miR-106ab and miR-17-92), and upregulating tumor suppressor microRNAs (eg, miR-1290, miR-149, miR-1908, miR1268, and miR-575) as demonstrated in literature and Figure 1.^24,31,32 Papers have also shown that resveratrol analogues can be effective in the treatment of PC. Regarding this issue, an experimental study evaluated the anti-tumor capacity of resveratrol and its analogues (piceatannol and trimethoxy-resveratrol) using cell proliferation and colony formation assays in vitro and in vivo. ³³ In the end, it was observed that trimethoxy-resveratrol, whose increased tissue and serum accumulation was demonstrated, is the most active compound in suppressing cell proliferation in vitro. Besides, pretreatment with the resveratrol and its analogues (for two weeks) reduced tumor volume and cell growth and colonization and suppressed the secretion of inflammatory cytokine IL-6 in a xenograft mouse model of PC. Intriguingly, both two analogues of resveratrol showed their inhibition of tumor progression, which was better than resveratrol. ³³ Together with the beneficial effects of resveratrol and its analogues, there is promising news regarding the anti-carcinoma impacts of nano-based formulations of resveratrol for prostate malignancy. In a scientific attempt, Singh and co-workers applied a receptor-based targeted delivery method by ball-milled nanoparticles (PBMNPs) conjugated with folic acid (FA) for loading resveratrol or a combination of docetaxel and resveratrol to treat PC in vitro. ³⁴ The findings resolved that neither resveratrol nor docetaxel can give rise to remarked suppression of PC cells (NCaP, C4-2 B, and PC3) resistant to drugs. On the contrary, the utilization of conjugated PBMNPs for encapsulating both resveratrol and docetaxel not only improved the bioavailability of these two drugs but also abrogated multidrug resistance (MDR) and dramatically suppressed cell growth. The Flow cytometry results revealed a considerable elevation in the apoptotic cell number by 30.92% and 65.9% in the conjugated nanoformulations loaded with resveratrol and the combination of resveratrol and docetaxel, respectively. In addition, the expressions of COX-2 (an inflammatory marker), NF-kB p65 (a cell survival marker), and anti-apoptotic genes (Bcl-xL, Survivin, and Bcl-2) were significantly lowered, but the expressions of pro-apoptotic genes (Bak and Bax) were increased following cancer therapy with nano-based formulation of two combined drugs. ³⁴ Another anticancer choice for targeted delivery of resveratrol can be mesoporous silica nanoparticles (MSNs), which are considered a suitable drug delivery platform in light of their flexibility and high capacity to load drugs. ³⁵ In this line, Chaudhary and colleagues loaded resveratrol onto amine and phosphonate-modified MSNs (∼60 nm) to potentiate its antiproliferative activity against PC cells (PC3 cell line). MSNs modified with the phosphonate group dramatically promoted the antiproliferative capacity of resveratrol (IC50 = 7.15 μM) compared with free resveratrol (IC50 = 14.86 μM). However, MSNs modified with the amine group didn't influence cancer cell proliferation despite having IC50 value more than free resveratrol (IC50 = 20.45 μM). ³⁵ Overall, these data highlight the pivotal role of resveratrol in attenuating PC cell survival, proliferation, growth, migration, invasion, and metastasis through different mechanisms. Also, it seems that the analogues and nanoformulations of resveratrol can be better strategies for PC treatment; however, further research work in preclinical and clinical studies are to be undertaken to confirm these results.

Figure 1.

Anti-Cancer Mechanisms of Resveratrol Against Prostate Cancer.

Table 1.

In Vitro and in Vivo Studies of Resveratrol and Prostate Cancer.

Resveratrol or its analogues/nano-based formulations	Resveratrol dose/concentration	Target (s)	Effect/mechanism (s)	Species	Cell line	Ref.
Resveratrol	50-100 mg/kg and 0-25 µM	PSA, BCHE, FOX3A, FRAP, PIK3R3, IGF-1R, STK39, and CDKN1A	Postponing tumor growth, increasing angiogenesis, and suppressing apoptosis	Athymic nude mice	LNCaP	28
Resveratrol	0-30 µM	PSA, AR, p21, p27, cyclin A, cyclin E, and CDK2	Suppressing DNA synthesis	-	LNCaP and DU145	36
Resveratrol	35, 70, and 140 µM	CD29, CD49b, CD44, DCLK1, OCT4, SOX2, CXCR4, Vimentin, and E-cadherin	Reducing cell viability and repressing EMT	-	PC-3	37
Resveratrol	0-40 µM	MMP-2, VE-cadherin, EphA2, and Akt	Repressing cell invasion and the formation of vasculogenic mimicry tube	-	PC-3 and DU145	38
Resveratrol	625 mg/kg	IGF-1, p-ERK1/2, and AR	Reducing cell proliferation	Male C57BL/6 mice	-	39
Resveratrol	50, 100, and 200 µg/mL	AR, Gk11, cleaved caspase-3 and -7, cyclin D1, and Bcl-xL	Repressing cell growth, stimulating apoptosis, and reducing the development of neoplastic lesions	Male heterozygous TRAP	-	40
Resveratrol	0-150 μM	Cyclin D1, cyclin E, cyclin B1, CDK1, p53, p27, p21, caspase-8 and -9, Bax, and Bcl-2	Stimulating apoptosis, arresting cell cycle, and repressing cell growth	-	LNCaP and PC-3	41
Resveratrol	20 µM	mTOR, Akt, PI3K, FOXO, TRAIL, Bim, DR4, and DR5	Stimulating apoptosis	-	LNCaP	42
Resveratrol	0-50 μM	E-cadherin, Vimentin, and Gli1	Reversing EMT, repressing cell invasion, and decreasing cell proliferation	-	LNCaP and PC-3	43
Resveratrol	50 μM	p21, p53, p15, cyclin B, CDK2, cyclin D, TRAILR1, and Fas	Repressing cell proliferation and enhancing apoptosis and cell senescence	-	PC-3	44
Resveratrol	0-75 μM	TRAF6, NF-κB, SLUG, Vimentin, and E-cadherin	Repressing cell proliferation and migration	-	PC-3 and DU145	45
Resveratrol	25 μM	p21, CDK4, and cyclin D1	Inhibiting cell growth and arresting cell cycle	-	WPE1-NB26, WPE1-NB14, WPE1-NA22, and RWPE-1	46
Resveratrol	25 μM	PCAT29, STAT3, IL-6, PDCD4, and miR-21	Reducing cell viability and proliferation	-	LNCaP and DU145	47
Resveratrol	10 µM	HIF-1	Postponing cell growth	-	PC-3 and LNCaP	48
Resveratrol	0-100 µM	ARV7	Repressing cell growth		PC-3	49
Resveratrol	1-100 μM	AR and PSA	Repressing cell proliferation and growth	-	LNCaP, Du145, and PC-3	50
Resveratrol	0-200 μM	DDX5 and mTORC1	Stimulating apoptosis and repressing cell growth	-	DU145 and PC-3	51
Resveratrol	25-100 µM	PSA, AR, Akt, and ARV7	Repressing cell proliferation and stimulating apoptosis	-	LNCaP	52
Resveratrol	0-50 µM	COX-2, pSer-15-p53, and pERK1/2	Repressing cell proliferation	-	LNCaP	53
Resveratrol	0-100 µM	mTOR, Akt, CHOP, GRP78, LC3B-II, and STIM1	Stimulating autophagy, repressing cell proliferation and viability, and inducing endoplasmic reticulum stress	-	DU145 and PC-3	54
Resveratrol analogue HS-1793	25-100 μM	VEGF, HIF-1α, PI3K, and Akt	Repressing cell migration	-	PC-3	55
Resveratrol and its combination with ionizing radiation	5 mg/kg and 0-1000 μg/mL	p-γ-H2AX, p- CHK2, p- ATM, p-p53, caspase-3, and PARP	Inducing cell death, repressing cell proliferation, decreasing cell viability, elevating radiosensitivity, and suppressing tumor growth	Male nude mice	PC3-KD and LAPC4-KD	56
Pure resveratrol and resveratrol encapsulated in liposome	50 mg/kg and 10 μM	Cyclin D1, AR, mTOR, and p-Akt	Deceasing body wight, repressing cell growth, and stimulating apoptosis	Male B6C3F1/J mice	PTEN-Cap8	57
Resveratrol encapsulated in polymeric nanoparticles	0-50 μM	Caspase-3	Decreasing cell viability and stimulating apoptosis	-	LNCaP	58
Resveratrol and Docetaxel co-delivery by PEGylated nano-liposomes	5.65 mg/kg and 18.3 μg/mL	Caspase-3	Repressing tumor growth and stimulating apoptosis	Balb/c nude mice	DU145 and PC-3	59
Resveratrol loaded onto surface modified mesoporous silica nanoparticles	10, 15, and 20 µM	-	Repressing cell proliferation and decreasing cell viability	-	PC-3	35
Planetary ball milled nanoparticle loaded with resveratrol	3 μM	Caspase-3, Bak, Bax, Bcl-2, Bcl-xL, Survivin, MDR-1, MRP-1, ABCG2, COX-2, and NF-kB p65	Inducing apoptosis and reducing cell proliferation	-	PC-3, LNCaP, and C4-2 B	60
Resveratrol nano formulation	_	ROS, NF-kB p65	Increase of apoptosis and Inhibition of abnormal NF-kB	_	PC3	61
Resveratrol	4.4 μg	_	Increase of prostate specific antigen doubling time (PSADT), reduction of cancer cells aggression and the risk of metastasis	_	PC3	62

Resveratrol and Bladder Cancer

Bladder cancer (BC), is the most frequent malignancy of the urinary system, and is the fourth most common cancer in men and 11th in women.^63,64 BC is mainly classified into nonmuscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). ⁶⁵ For this cancer, different therapies (eg, radical cystectomy, radiotherapy, and chemotherapy) have been offered; however, these cancerous cells have the capacity to resist treatments. ⁶⁶ Fortunately, several preclinical papers have shown that using natural-based products, especially resveratrol, can pave the way for treating BC. ⁶⁷ In this line, researchers have focused on a lot of therapeutic processes of resveratrol against this common type of urinary system cancer (Table 2). For instance, Wang et al deliberated on the effects of resveratrol (0-350 µM) and other natural compounds (epigallocatechin gallate and ginsenoside Rh2) on multidrug resistance (MDR), a main obstacle for successful cancer therapy, in human BC cells (pumc-91) resistant to adriamycin (ADM) in vitro by assessing the protein and mRNA expression levels of drug resistance-related proteins, comprising topoisomerase-II (Topo-II), B cell leukemia/lymphoma-2 (Bcl-2), glutathione S-transferase (GST), lung resistance protein (LRP), and multidrug resistance protein 1 (MRP1) by immunofluorescence and reverse transcription-quantitative polymerase chain reaction assays, respectively. ⁶⁸ This study revealed the reversing role of resveratrol in drug resistance in BC, as evidenced by a remarked reduction of Bcl-2, GST, LRP, and MRP1 levels and the elevation of Topo-II levels in comparison with the control group. ⁶⁸ Anti-apoptotic influences of Bcl-2 protein have a key role in MDR, and GST develops drug resistance through direct detoxification.^69,70 LRP is involved in drug resistance by extruding drugs from the nucleus to the cytoplasm by vesicular trafficking; also, MRP1, as an efflux pump, expels different anticancer drugs from the desired cancer cells.^71–73 On the other hand, the decreased sensitivity and function of Topo-II are important for drug resistance promotion. ⁷⁴ Other findings of this research addressed cell cycle arrest at the S phase along with a reduction in the number of cells at the G1 phase and cell growth suppression upon resveratrol therapy. ⁶⁸ Almeida et al explored toxicogenomic and antiproliferative aspects of resveratrol (12.5-250 μM) in BC cells with diverse TP53 status (grade1, p53 wild-type RT4; 5637-grade 2 and T24-grade 3, TP53 mutated) in vitro. ⁷⁵ In this work, resveratrol stimulated DNA damage and reduced cell proliferation in BC cells. Concerning the long-term influences, resveratrol could decrease colony formation of BC cell lines. TP53 wild-type cells underwent considerable apoptosis together with the downregulation of SRC, mTOR, and Akt. The antiproliferative effects of resveratrol on wild-type TP53 cells were along with DNMT1 gene regulation. Also, there was a cell cycle arrest at the S phase with downregulation of the PLK1 gene in the TP53 mutated cells. Moreover, nuclear PCNA attenuation and HOXB3/RASSF1A pathway regulation were reported in BC cells in the highest grade. ⁷⁵ RASSF1A, as a tumor suppressor, is silenced through its promoter region hypermethylation in a wide spectrum of cancers, such as BC. ⁷⁶ RASSF1A suppression takes place through the oncogene HOXB3, stimulating the expression of the DNMT3B gene encoding the enzymes that have a substantial role in DNA methylation. ⁷⁷ In an in vitro (T24 cell lines) and in vivo (male BALB/c-nude mice) investigation, the chemopreventive capacity of resveratrol against BC at doses of 0-250 μM and 20 mg/kg, respectively, was scrutinized. ⁷⁸ From a more exact view, the in vitro findings addressed apoptosis induction by regulating Bcl-2 family proteins and triggering caspase-3 and −9 and subsequently degrading poly(ADP-ribose) polymerase (PARP). Furthermore, resveratrol therapy caused cell cycle arrest at the G1 phase in T24 cells by downregulating cyclin-dependent kinase 4 (CDK4), cyclin D1, and phosphorylated Rb and activating p21. This natural product also suppressed Akt phosphorylation, while p38 MAPK phosphorylation was promoted. The in vivo outcomes reflected tumor growth suppression, possibly by reducing the expression of fibroblast growth factor-2 (FGF-2) and VEGF. ⁷⁸ In another in vitro and in vivo research performed by Wu et al, the cell line model was established by exposing human TCC EJ cells to 100-200 µM resveratrol to imitate intravesical drug injection. The analyzed data exhibited that the administration of 150 or 200 µM resveratrol (for 2 h) causes remarked apoptosis and cell cycle arrest at the S phase along with decreased phosphorylation, nuclear translocation, and transcription of STAT3 (Figure 2), the attenuated expression of VEGF, c-Myc, cyclinD1, and Survivin (STAT3 downstream genes), and nuclear translocations of p53 and Sirt1. In the mentioned work, an orthotopic nude mouse model was designed through the injection of EJ cells into the sub-urothelial layer, and then 50 µl of 200 µM resveratrol was administrated; consequently, similar findings were reported. ⁷⁹ In a distinct study, structure-function association and metabolic status of resveratrol (trans-resveratrol) and its analogues (acetyl resveratrol, oxyresveratrol, and polydatin) in human BC cells (T24 cells) were examined to suggest a suitable formulation of resveratrol with enhanced bioavailability to fight this cancer. ⁸⁰ To appraise the influences of resveratrol and its analogues on BC viability, T24 cells were exposed to various concentrations of drugs (0-200 μmol·L⁻¹). Finally, the outcomes of the MTT test demonstrated that, except for polydatin, with elevating concentrations of drugs at certain time points, resveratrol, oxyresveratrol, and acetyl resveratrol suppress cell growth in a time- and dose-dependent approach (oxyresveratrol > acetyl resveratrol > resveratrol > polydatin). The next step in this project was to investigate the effects of these compounds on apoptosis. In this respect, it was unveiled that resveratrol, oxyresveratrol, and acetyl resveratrol can stimulate this type of programmed cell death in T24 cells; however, polydatin did not reflect the apparent apoptosis-stimulating influence on T24 cells. HRMS, LC-MS/MS, and HPLC analyses revealed that resveratrol is the main metabolite during the metabolic occurrence of acetyl resveratrol. Furthermore, resveratrol concentration in acetyl resveratrol-incubated T24 cell lysate was increased compared with the resveratrol-incubated group, showing the better absorption of acetyl resveratrol and the protective role of acetyl groups for the phenolic hydroxyl groups from glucuronidation or sulfation, and eventually its good bioavailability and biopotency. ⁸⁰ Overall, it seems that resveratrol can be useful in BC therapy by targeting molecular and cellular occurrences, like stimulating apoptosis, elevating oxidative stress, and reducing ATP concentration, as well as reversing drug resistance. Besides, the analogues and nano-based carriers of resveratrol can be suitable formulations for this therapeutic purpose.

Figure 2.

Anti-Cancer Mechanisms of Resveratrol Against Bladder Cancer.

Table 2.

In vitro and in vivo Studies of Resveratrol and Bladder Cancer.

Resveratrol or its analogues/nano-based formulations	Resveratrol dose/concentration	Target (s)	Effect (s)	Species	Cell line	Ref.
Resveratrol	0.1-100 µM	Bcl-2, Bad, NO, and PGE2	Stimulating cell death and decreasing cell growth (at high concentrations)	-	ECV304	81
Resveratrol	20 mg/kg and 0-200 µM	p21, cyclin D1, CDK4, phosphorylated Rb, Akt, p38 MAPK, VEGF, FGF-2, Bcl-xL, Bcl-2, Bad, caspase-3, and PARP	Stimulating apoptosis and decreasing tumor growth	Nude mice	T24	78
Resveratrol	50 µl of 200 µM and 100-200 µM	STAT3, VEGF, c-Myc, cyclinD1, Survivin, p53, and Sirt1	Stimulating apoptosis, arresting cell cycle, and repressing cell and tumor growth	Nude mice	EJ	79
Resveratrol	0-350 µM	Bcl-2, GST, LRP, and MRP1	Reversing drug resistance, arresting cell cycle, and repressing cell growth	-	Pumc-91/ADM	68
Resveratrol	12.5-250 μM	SRC, mTOR, Akt, DNMT1, RASSF1A, HOXB3, and PLK1	Reducing cell proliferation and stimulating DNA damage and apoptosis	-	T24, 5637, and RT4	75
Resveratrol	0-50 μM	miR-21, Bcl-2, Akt, and caspase-3	Stimulating apoptosis and cytotoxicity	-	5637 and T24	82
Resveratrol	0-50 µM	MMP-2 and -9, ERK1/2, and JNK1/2	Repressing cell invasion, migration, and adhesion	-	T24	83
Resveratrol	12.5-200 μM	SMAD4, CDH1, and CTNNB1P1	Elevating ROS formation, repressing cell migration, and decreasing cell viability and proliferation	-	T24, 5637, and RT4	18
Resveratrol	2.5-100 mmol/L	Cytochrome c and caspase-3 and -9	Stimulating apoptosis, reducing cell viability, disrupting mitochondrial membrane potential, elevating ROS formation, and decreasing ATP concentration	-	T24 and BTT739	84
Resveratrol and its analogs including acetylresveratrol, xyresveratrol, and polydatin	0-200 µM	-	Exerting considerable morphological changes and apoptotic and inhibitive effects except polydatin	-	T24	80
Combination of resveratrol and rapamycin	100 µM	PDCD4, p-S6K1, p-mTOR, p-S6, p-4EBP, p-eIF4B, p-Akt, PRAS40, capase-3, PARP, mcl-1, and surviving	Stimulating apoptosis and repressing cell survival, migration, and growth	-	639 V, MGH-U1, and HCV29	85
Combination of resveratrol and Doxorubicin	150-250 µM	-	Reducing cell migration and increasing ROS	-	T24 and 5637	86
Nanoemulsion loaded with resveratrol	25 and 50 µM	-	Inducing oxidative stress and decreasing cell viability	-	T24	87

Resveratrol and Renal Cell Carcinoma

After prostate and bladder cancers, renal cell carcinoma (RCC), the most common cancer of the kidney, is ranked the third most prevalent cancer among urologic malignancies.^88,89 RCC is mainly divided into several subtypes comprising papillary RCC types 1 and 2, clear cell RCC, mixed oncocytoma, or chromophobe RCC. ⁹⁰ Dissimilar to other malignancies, there are insufficient prognoses and biomarkers for RCC,^91,92 and RCC cases show resistance to conventional treatments, such as chemotherapy and radiation therapy.^93,94 Thus, finding novel therapeutic agents and potentials remains a priority for RCC treatment. ⁹⁵ In recent years, multiple studies have been accomplished to evaluate the therapeutic effects of resveratrol against RCC in vitro and in vivo (Table 3).^96,97 In an in vitro study performed by Kim et al on RCC cell lines, 786-O and Caki-1 cell lines, it was approved that resveratrol suppresses the phosphorylation and activation of STAT3 and STAT5, which are related to the inhibition of the upstream kinases (namely, c-Src and JAK1/2), in a concentration-dependent manner. ⁹⁸ STAT proteins, like SAT3 and STAT5, are over-expressed in many cancers, such as renal cancer, and have a regulatory role in apoptosis inhibition and cell proliferation.^99,100 Kim and colleagues also showed that after 24 h of treatment with resveratrol, the reduction of the potential of mitochondrial membrane and induction of mitochondrial dysfunction occur through the suppression of IAP-1, IAP-2, Survivin, Bcl-2, and Bcl-xL and activation of caspase-3 leading to early and late apoptosis in RCC cells (Figure 3). ⁹⁸ In addition, they found that resveratrol induced cell cycle development inhibition by increasing p21 and decreasing cyclin D1 and cyclin E expressions. Resveratrol also remarkably attenuated tumor invasion through suppression of cyclin D1, VEGF, and MMP-9, which are modulated through STAT3.^98,101–103 In in vitro study carried out by Zhao et al, the remarkable inhibitory effects of resveratrol at various doses (10-200 μM) on proliferation, migration, and metastasis of RCC cells, ACHN and A498 renal cell lines, were demonstrated by mediation of ERK1/2 and Akt signaling pathways. ¹⁰⁴ From a more detailed view, resveratrol attenuated the expression of phosphorylated ERK1/2 and Akt protein levels, EMT markers (eg, vimentin and N-cadherin), tumor metastasis markers (MMP-2 and −9), and transcriptional repressors (snail), while elevated the levels of cell invasion suppressors, including tissue inhibitors of metalloproteinase 1 (TIMP1-1) and E-cadherin proteins in a time- and dose-dependent manner in both cell lines. They also expressed that treatment with resveratrol suppressed the production of filopodia, actin-rich plasma-membrane micro spikes, ¹⁰⁵ which have a crucial role in cell migration. ¹⁰⁴ Tian and co-workers designed another experimental study to find out the underlying molecular mechanism of antitumor properties of resveratrol in RCC in vitro and in vivo. ¹⁰⁶ They observed that resveratrol at 100 μM (for 24 h) had the maximum antitumor effects on both 786-O and ACHN cell lines. They also stated that at this concentration, resveratrol significantly promoted apoptosis (by increasing Bax/Bcl-2 ratio), suppressed cell migration and invasion through downregulation of NLRP3 (nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3) inflammasome and its downstream genes in both cell lines compared to saline group. The in vivo results of this experiment implicated that resveratrol administration considerably repressed tumor growth since the 32th day of treatment, and RCC mice in the resveratrol group all survived on day 40 compared to the control (saline) group. ¹⁰⁶ NLRP3 has been found to be extremely upregulated in RCC and has a pivotal role in caspase-1–associated maturation of the proinflammatory factors (eg, IL-18 and IL-1β) in tumor microenvironment.^107,108 Interestingly, a combination therapy with resveratrol and TNF-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) superfamily, ¹⁰⁹ was inspected by Zeng et al in vitro and in vivo in 2020. ¹¹⁰ TRAIL possesses cytotoxic effects on tumor cells and induces apoptosis selectively in cancer cells without harmful impacts on normal cells. ¹¹¹ In order to evaluate the synergistic effects of TRAIL and resveratrol in vitro, Zeng et al found that resveratrol (100 μM) synergistically enhanced the apoptotic effects of TRAIL (200 ng/mL) on both OS-RC-2 and 786-0 cell lines. The analysis done with transmission electron microscopy provided evidence that the combination of TRAIL and resveratrol stimulates apoptosis and autophagy in RCC cells. Further assessments by the Western blot test indicated that the apoptosis in this occurrence is a caspase-dependent process with the involvement of caspase-3, caspase-8, and caspase-9. For an in vivo evaluation, they obtained Ad5/35-TRAIL, a fiber-modified replication-deficient adenovirus, and addressed that Ad5/35-TRAIL besides resveratrol remarkably suppressed tumor growth in nude mice. ¹¹⁰ Other pre-clinical reports have also proposed a number of anticancer mechanisms of resveratrol against RCC, including suppression of the PI3K/AKT signaling pathway, increment of reactive oxygen species (ROS) as a trigger for apoptosis and autophagy, and promotion of histone acetylation.^97,112,113 In addition to resveratrol, the anti-RCC potential of the analogues of this polyphenol (ie, DMU-212 and HS-1793) has been exhibited through similar mechanisms.^112,114 Also, harnessing nano-based products of resveratrol to conquer its pharmacological challenges and elevate the therapeutic effectiveness has been suggested. Regarding this matter, a recent scientific project investigated the impacts of resveratrol nanoparticle-based therapy on RCC and focused on involved mechanisms in vitro. ¹¹⁵ Finally, the authors explained that this nano-based formulation inhibits cancer cell invasion and migration in ACHN and A498 cells through down-regulation of MMP-2 and up-regulation of tissue inhibitor of metalloproteinases 2 (TIMP-2) in a dose-dependent way. Furthermore, resveratrol nanoparticles suppressed the p-ERK1/2 signaling pathway but had no impact on p-JNK and p-p38. ¹¹⁵ Altogether, resveratrol nanoparticles suppressed the survival, invasion, and migration of RCC cells through inhibition of MMP-2 expression and ERK signaling pathway. ¹¹⁵ It deems that resveratrol can positively affect RCC like PC and BC; moreover, using alternative formulations of this polyphenol, namely its analogues or nano-based products, can promote its efficiency against RCC.

Figure 3.

Anti-Cancer Mechanisms of Resveratrol Against Renal Cell Carcinoma.

Table 3.

In vitro and in vivo Studies of Resveratrol and Renal Cell Carcinoma.

Resveratrol or its analogues/nano-based formulations	Resveratrol dose/concentration	Target (s)	Effect/mechanisms (s)	Species	Cell line	Ref.
Resveratrol	25 and 50 μM	BGPa, MDM2A, GADD45, MDM2, MDM2E, RBP1, VDR, CSF1, IL-8, β-HCG, CRABP-II, TRAF-1, PAI-1, TNFAIP3, RelB, ATF3, HCK, GFRα2, IGFBP-5, HGF, CYP1B1, MUC1, and CXCR4	Stimulating the expression of genes associated with cell death and inhibiting cell growth	-	RCC54	116
Resveratrol	10-200 μM	Snail, Vimentin, N-cadherin, MMP-2 and -9, p-ERK1/2, p-Akt, TIMP-1, and E-cadherin	Repressing cell proliferation, migration, and invasion	-	A498 and ACHN	104
Resveratrol	60 mg/kg and 25-100 μM	NLRP3, Bcl-2, Bax, IL-6, IL-1β, caspase-1 and -3, and E-cadherin	Repressing cell proliferation, migration, and invasion and stimulating apoptosis	Male nude mice	786-O and ACHN	106
Resveratrol	0-50 μM	Akt, p-Akt, p-PI3K, PI3K, and Survivin	Attenuating chemoresistancy, stimulating apoptosis, and suppressing cell growth	-	Caki-1	97
Resveratrol	0-100 μM	Bcl-2, Bax, AMPK, mTOR, p53, LC3, ATG5, and ATG7	Repressing cell migration and viability and inducing apoptosis and autophagy	-	Ketr-3 and HK-2	117
Resveratrol	10, 20, and 40 µM	Caspase 3, PARP, LC3B II, ERK, p38, and JNK	Repressing cell viability and stimulating apoptosis and autophagy	-	786-O	112
Resveratrol	0-50 μM	STAT3, STAT5, c-Src, JAK1, JAK2, SHP-2, PTPε, caspase-3, Survivin, Bcl-xL, Bcl-2, IAP-1, IAP-2, COX-2, MMP-9, and VEGF	Arresting cell cycle, stimulating apoptosis, and repressing colony formation and cell viability and invasion	-	786-O and Caki-1	118
Resveratrol	1, 2.5, and 5 mg/kg	Fas, FasL, IFN-γ, IL-6, IL-10, granzyme B, and perforin	Suppressing tumor growth, decreasing immune suppression, and suppressing angiogenesis	Female BALB/c mice	-	119
Resveratrol	0-62.5 μg/mL	MMP-2 and -9, acH3K9, acH3K14, acH4K12, acH4K5, and acH4K16	Repressing cell viability, migration, invasion and cell cycle	-	ACHN	113
Resveratrol	0-200 μM	COX-2, VEGF, AT1R, AngII, Bax, Bcl-2, and caspas-9	Repressing cell growth and stimulating apoptosis	-	A498 and ACHN	120
Resveratrol	0-40 μM	VEGF	Suppressing cell proliferation and growth	-	786-0	103
Cis-resveratrol and trans-resveratrol	0-100 μM	p53	Elevating cytotoxicity in cancer cells	-	SN12C and A498	121
Resveratrol analogue HS-1793	0-25 μM	Bcl-2, PML, Sp100, Daxx, and SUMO-1	Stimulating apoptosis, forming mature PML nuclear bodies, and decreasing cell viability	-	Caki-1	122
Combination of TRAIL and resveratrol and combination of resveratrol and Ad5/35-TRAIL	200 mg/kg and 100 μM	Caspase-3, -8, and-9, XIAP, and PARP	Sensitizing to TRAIL-related death and suppressing tumor growth	Nude mice	OS-RC-2 and 786-0	123
Combination of sorafenib and PEGylated resveratrol	200 μmol/kg and 10-640 mmol/L	HIF-lα, p-mTOR, p-Akt, p70S6k-4EBP-1, p-ERK, p-MEK, p-c-Raf, Bax, and Bcl-2	Repressing cell proliferation and migration and tumor growth and enhancing the proliferative capacity of inactivated splenic lymphocytes and the lymphocytes induced by lipopolysaccharide and concanavalin A	Male BABL/c mice	786-O	124
Resveratrol nanoparticles	0-80 μM	MMP-2, TIMP-2, p-ERK1/2, p-JNK, and p-p38	Repressing cell viability, migration, and invasion	-	A498 and ACHN	19

Resveratrol and Testicular Cancer

Testicular cancer (TC) is another common neoplasm related to the urological system with considerable mortality and morbidity in men at young ages and is responsible for 10 000 death cases per year worldwide. ¹²⁵ Some researchers have indicated the anti-neoplasm capacity of resveratrol in TC directly or indirectly. In this line, Chen et al inspected the effect of resveratrol as a phytoestrogen on the steroidogenesis of MA-10 cells, a cell line originating from mouse Leydig tumor cells. ¹²⁶ They found that the incubation of MA-10 cells with 50 μM of this phytoestrogen leads to the suppression of progesterone release through the mRNA expression reduction of steroidogenic acute regulatory (StAR) induced by Cyclic AMP in this testicular murine tumor-related cell line. ¹²⁶ Leydig cell tumor is an uncommon neoplasm emerging as a testicular mass with or without endocrine alterations. ¹²⁷ In this testicular tumor, the secretion of steroid hormones, including progesterone, testosterone, and estrogen, has been approved as one of the pathogenic mechanisms. ¹²⁸ StAR is an important regulatory protein with a pivotal function in conveying cholesterol into the mitochondria for steroidogenic activities and serves as a biomarker of Leydig cell tumors. ¹²⁹ Another related effort has recently been made by Mitra and co-workers in vivo. They implicated the upregulation of the proteins pertained to testicular germ cell neoplasia in situ (GCNIS) and Akt cascade in mice tissues subjected to Pb(CH₃COO) ₂ (3 and 6 mg/kg) and cadmium chloride (0.25 and 0.5 mg/kg) compared with the health group. ¹³⁰ On the other hand, resveratrol administration (20 mg/kg) could attenuate metal-conferred disruption of spermatogenesis, Akt cascade proteins (COX-2, NF-kB, and p-Akt) accompanied by GCNIS markers. ¹³⁰ GCNIS is defined as a malignant testicular germ cell tumor precursor and expresses some markers comprising c-Kit and Oct 3/4. ¹³¹ Also, Akt signaling has a substantial role in cellular activities, like apoptosis, proliferation, and protein synthesis, and its aberrant regulation has been detected in tumorigenesis. ¹³⁰ The current evidence shows that resveratrol may target testicular cancer by regulating the secretion of steroid hormones and Akt signaling; however, more investigations are needed to approve this result and find other therapeutic mechanisms.

Resveratrol Limitations

Although resveratrol has several biological and therapeutic activities, there are some pharmacological limitations for this natural polyphenol that may affect its effectiveness in diseases. These limitations include its weak solubility in water, poor bioavailability, restricted stability, and a high rate of metabolization. ⁹ An extensive metabolism in the intestine and liver has even yielded resveratrol bioavailability of less than 1%. ¹³² However, bioavailability can be enhanced by various delivery systems such as chemical modification (to change chemical structure) and encapsulation approaches.^133–135

In addition to the mentioned pharmacological challenges, there has to be enough caution for using resveratrol mainly at inappropriate doses. Even though resveratrol can be considered a safe and well-tolerated compound, there is evidence indicating that it may be cytotoxic or harmful at high concentrations in vivo and in vitro. ¹³⁶ Toxicological reports revealed that resveratrol administration at high doses in animal studies can cause nephrotoxicity. ¹³⁷ In the work of Crowell et al ¹³² to explore resveratrol cytotoxicity, rats received 0, 300, 1000, and 3000 mg/kg trans-resveratrol daily for 4 weeks. In evaluated animals, the most detrimental effects related to toxicity, such as decreased food consumption and body weight and increased creatinine, blood urea nitrogen (BUN), alanine aminotransferase, alkaline phosphatase, total bilirubin, and white cell levels, were observed following resveratrol usage at the dose of 3000 mg/kg. ¹³⁸ In vitro results have also shown that this natural product can postpone the healing processes of gastric lesions and exacerbate cardiac damage induced by ischemic reperfusion at high concentrations. ¹³⁶ Besides, scientific data pointed out the adverse influences of resveratrol after its intake at high doses in human studies.^139–141 As an example, in the investigation of Boocock et al, ¹³⁴ it was addressed that out of 40 cases who were treated with 1 g resveratrol, 2 subjects experienced a slight increase in the levels of alanine aminotransferase and blood bilirubin. ¹⁴⁰ Another research team declared three adverse events related to treatment with resveratrol, including erythematous rash, nasopharyngitis, and blood electrolyte changes, in 3 patients of 24 studied patients. ¹³⁹ Biosafety of resveratrol also was tested in a clinical trial that was evaluated in 40 healthy volunteers. Intake of resveratrol in doses of 0.5, 1.0, 2.5, and 5.0 g/d in 29 days was found to be safe. ¹⁴² Other researches indicated that high dose or long-term administration of this compound may lead to the suppression of cytochrome P450, a membrane-bound hemoprotein detoxifying drug, and thyroid disruption.^143–146 This evidence emphasizes the importance of resveratrol therapy at optimal doses and a suitable time framework for therapeutic purposes.

Resveratrol and Clinical Trials

Clinically, scientists also explored the anticancer impacts of resveratrol on some cancer, such as colorectal cancer, gastric cancer, breast cancer, and skin cancer (Table 4), and the results of some of these have not been published yet (https://clinicaltrials.gov). One of the published clinical papers regarding the anti-neoplasia effects of resveratrol and its metabolite on colorectal cancers has been undertaken by Patel and co-workers. ¹⁴⁷ In this work, for 20 cases with histologically identified colorectal cancer, resveratrol at the dose of 0.5 or 1.0 g orally for 8 days was prescribed before surgical resection. Resveratrol along with its metabolites, comprising resveratrol disulfate, resveratrol sulfate glucuronide, resveratrol-4′-O-sulfate, resveratrol-3-O-sulfate, resveratrol-4′-O-glucuronide, and resveratrol-3-O-glucuronide, was detected in resected colorectal tissues by high-pressure liquid chromatography (HPLC) with mass spectrometric or UV identification. Resveratrol and one of its metabolites (resveratrol-3-O-glucuronide) were determined from tissues at maximal average levels (674 and 86.0 nmol/g, respectively). Moreover, resveratrol consumption decreased the proliferation rate of tumor cells by 5%. ¹⁴⁷ Recently, a single-arm phase II study was conducted to examine the effectiveness of combination therapy with copper and resveratrol on the toxicity of chemotherapy based on docetaxel in the advanced stage of gastric cancer. For this purpose, 30 patients were pursued (between October 2019 and April 2021). Eventually, it was inferred that the administration of the combination of copper and resveratrol ameliorates chemotherapy-associated non-hematological toxicities, like diarrhea, vomiting, and hand-foot syndrome, in patients with gastric cancer at the advanced stage. ¹⁴⁸ In another relevant project, 19 breast cancer patients consumed polyphenol-rich capsules containing the extracts of grape seed (53.85 mg), cocoa (161.5 mg), olive (161.5 mg), lemon (53.85 mg), orange (53.85 mg), pomegranate (161.5 mg), as well as trans-resveratrol (53.85 mg); ¹⁴⁹ then, their metabolite profile was assessed. The patients were trained to take the supplements from the verified cancer diagnosis to the day of the initiation of surgery. Phenolic metabolites in healthy and malignant tissues were dominantly sulfated and glucuronidated. The results of this investigation manifested that these metabolites do not possess estrogenic/antiestrogenic or antiproliferative functions in breast cancer cells (MCF-7). ¹⁴⁹ Regarding the clinical aspects of resveratrol therapy in urological cancers, some related clinical studies have been published.^150,151 In this regard, a clinical trial study was conducted by Paller et al on 14 patients with confirmed prostate adenocarcinoma. In the phase I of this work, patients with biochemically recurrent PC were allocated to elevating doses of a commercial product consisting of pulverized muscadine grape skin (MPX), in which a 500 mg capsule form is composed of polyphenols (ie, 4.4 μg trans-resveratrol, 9.2 μg quercetin, and 1.2 mg ellagic acid). The used doses of MPX in this study were 500, 1000, 2000, 3000, and 4000 mg. In the end, the authors observed the antitumor action of MPX, as evidenced by changes in prostate-specific antigen (PSA) doubling time. ¹⁵⁰ A more updated study appraised the outcomes of phytotherapy by administrating two tablets (two times per day) of resveratrol (30 mg), broccoli sprout concentrate, green tea leaf concentrate, and turmeric (Curcuma longa) rhizome extract in biochemically recurrent PC cases. ¹⁵¹ This double blind, randomized, placebo-controlled trial was performed to investigate 22 men with mentioned carcinoma for about 12 weeks. The involved patients were assigned to two groups of placebo and active (phytotherapy). The findings of performed tests indicated that phytotherapy-based intervention was well-tolerated. Moreover, the active group underwent an insignificant elevation in the log-slope of PSA, but the placebo group underwent no change in terms of the mentioned index (155). These data show that resveratrol can be effective in the clinic for fighting diverse cancers; however, concerning its effectiveness in urological cancers, more persuasive evidence is required.

Table 4.

Registered Clinical Studies Related to Resveratrol Therapy in Malignancies or Tumors. Reference: https://clinicaltrials.gov.

ID	Status	Malignancy/tumor	Used resveratrol	Enrolled subjects	Phase	Country
NCT01476592	Completed	Low grade gastrointestinal tumors	5 mg/day resveratrol orally	7	-	United States
NCT00256334	Completed	Colon cancer	20 and 80 mg/day resveratrol	11	Phase 1	United States
NCT03253913	Completed	Lymphangioleiomyomatosis	250 mg/day resveratrol for 8 weeks, then 500 mg/day for 8 weeks, and finally 500 mg twice a day for the last 8 weeks	25	Phase II	United States
NCT00433576	Completed	Colorectal cancer	-	20	Phase1	United States
NCT00920803	Completed	Colorectal Cancer	5 g micronized resveratrol (SRT501)	9	Phase1	United Kingdom
NCT03482401	Completed	Breast cancer	474 mg/day polyphenol supplement including resveratrol	40	-	Spain
NCT05306002	Active, not recruiting	Hereditary breast and ovarian cancer syndrome	Combination therapy with resveratrol and other natural compounds (eg, carotenoids, epigalactocatechin, curcumin etc)	34	-	Mexico
NCT05736224	Recruiting	Skin cancer	Sunscreen comprises bioadhesive nanoparticles (BNP) loaded with avobenzone and octocrylene plus some natural products including trans-resveratrol	30	Phase 1	United States

Conclusion

Urological cancers are among malignancies with high mortality and morbidity; thus, applying an efficient treatment against these serious illnesses is indispensable. The present scientific evidence reflects that resveratrol can be a good fighter against urological cancers through various cellular and molecular mechanisms. These mechanisms include repressing angiogenesis (by decreasing VEGF levels), modulating estrogen and androgen-related occurrences, epigenetic modifications (eg, downregulating oncogenic microRNAs and upregulating tumor suppressor microRNAs), attenuating EMT (by decreasing E-cadherin and Vimentin levels), arresting cell cycle (by downregulating CDK4, cyclin D1, and phosphorylated Rb and activating p21), stimulating apoptosis by elevating apoptosis-inducing agents (Bax and caspase-3 and −9), attenuating anti-apoptosis agents (survivin, Bcl-xL, and Bcl-2), degrading PARP, suppressing inflammatory-associated factors (eg, IL-6 and NLRP3), and attenuating drug resistance-related proteins (ie, Bcl-2, GST, LRP, and MRP1). Despite this, the utilization of resveratrol is accompanied by low bioavailability which is necessitated by poor solubility in water and high rate of metabolism in the intestine and liver. It has to be mentioned that to reach the expected therapeutic outcomes of this polyphenol, optimal doses and appropriate timelines are necessary to avoid possible toxic influences. Several researchers suggest that analogues and nanoformulations of resveratrol can be more efficient against these cancers compared with pure resveratrol by overcoming its pharmacological challenges such as low bioavailability and exerting similar therapeutic mechanisms. However, more preclinical and clinical investigations are still neededto confirm promising findings.

Abbreviation

LC3, Light chain 3; ATG, Autophagy related; TRAP, Transgenic Rat for Adenocarcinoma of Prostate; ARV7, Androgen receptor splice variant 7; PCAT29, Prostate cancer associated transcript 29; PDCD4, Programmed cell death protein 4; ANO1, Anoctamin1; DDX5, DEAD (Asp-Glu-Ala-Asp) box helicase 5; TRAF6, TNF-receptor associated factor 6; STIM1, Stromal interaction molecule 1; BGP, Biliary glycoprotein; MDM2A, Mouse double minute 2-A; GADD45, Growth arrest and DNA-damage-inducible protein 45; RBP1, Retinoblastoma binding protein 1 isoform I; VDR, Vitamin D receptor; CSF1, Granulocyte-macrophage colony-stimulating factor; IL, Interleukin; HCG, Human chorionic gonadotropin; CRABP-II, Cellular retinoic acid binding protein-II; TRAF, Tumor necrosis factor receptor; PAI-1, Plasminogen activator inhibitor-1; TNFAIP3, Tumor necrosis factor α inducible protein 3; RelB, V-rel reticuloendoiheliosis viral oncogene homolog B; ATF3, Activating transcription factor 3; HCK, Hemopoietic cell protein-tyrosine kinase, GFRα2, GDNF family receptor α 2; IGFBP-5, Insulin-like growth factor binding protein 5; HGF, Hepatocyte growth factor; CYP1B1, Cytochrome P450 1B1; MUC1, Mucin 1; CXCR4, Chemokine (C-X-C motif) receptor 4; ERK, Extracellular-signal-regulated kinase; TIMP, Tissue inhibitor of metalloproteinase; Bax, Bcl-2 associated X; PI3K, Phosphoinositide 3-kinase; AMPK, AMP-activated protein kinase; mTOR, Mammalian target of rapamycin; JNK, c-Jun N-terminal Kinase; JAK1, Janus kinase 1; SHP-2, SH2-containing protein tyrosine phosphatase-2; PTPε, Protein tyrosine phosphatase epsilon; IAP-1, Inhibitor of apoptosis protein-1; COX-2, Cyclooxygenase-2; Sirt1, Sirtuin 1; HIF-lα, Hypoxia inducible factor-1α; MEK, MAPK/ERK kinase; XIAP, X-linked inhibitor of apoptosis protein; PML, Promyelocytic leukemia; SUMO-1, Small ubiquitin like modifier 1; Daxx, Death domain-associated protein; AT1R, AngII type 1 receptor; AngII, Angiotensin II; acH3K, Acetylated histone H3 lysine; BCHE, Butyrylcholinesterase; FRAP, FKBP-12-rapamycin associated protein; PIK3R3, Phosphoinositide-3-kinase regulatory subunit 3; IGF-1R, Insulin-like growth factor 1 receptor; STK39, Serine/threonine kinase 39; CDKN1A, Cyclin dependent kinase inhibitor 1A; MDR-1, Multidrug resistance mutation 1; MRP-1, Multidrug resistance protein 1; ABCG2, ATP-binding cassette super-family G member 2; AR, Androgen receptor; CDK2, Cyclin-dependent kinase 2; p-γ-H2AX, Phosphorylated histone 2A family member X; CHK2, Checkpoint kinase 2; ATM, Ataxia telangiectasia mutated; SOX2, SRY (sex determining region Y)-box 2; OCT4, Octamer-binding transcription factor 4; DCLK1, Doublecortin like kinase 1; VE-cadherin, Vascular endothelial cadherin; EphA2, Erythropoietin-producing hepatocellular receptor A2; Gk11, Glandular kallikrein 11; DR4, Death receptor 4; Gli1, Glioma-associated oncogene-1; FasL, Fas ligand; IFN-γ, Interferon gamma; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; mTORC1, Mammalian target of rapamycin complex 1; GRP78, Glucose-regulating protein 78; CHOP, C/-EBP homologous protein; NO, Nitric oxide; PGE₂, Prostaglandin E₂; RB, Retinoblastoma; MAPK, Mitogen-activated protein kinase; FGF-2, Fibroblast growth factor 2; GST, Glutathione S-transferase; LRP, Lung resistance protein; DNMT1, DNA cytosine-5-methyltransferase 1; RASSF1A, Ras association domain family protein1 isoform A; HOXB3, Homo sapiens homeobox B3; PLK1, Polo-like kinase 1; CDH1, Cadherin 1; CTNNB1P1, Catenin beta interacting protein 1; PRAS40, Proline-rich Akt substrate of 40 kDa; EMT, Epithelial-mesenchymal transition; VGSC, Voltage-gated NaC channel; FBS, Fetal bovine serum.