Natural Environmental Sources of Resveratrol and Its Therapeutic Role in Cancer Prevention

Md Rahedul Islam¹, Tamanna Yesmin¹, Amatun Noor Prapty², Md Abdur Rahman Biswash³, Md Sohel Rana⁴, Md Haroon Or Rashid^5* 

Resveratrol's potential in cancer therapy highlights its importance as a promising adjunct treatment, improving efficacy and reducing side effects.

Abstract

Resveratrol, a polyphenolic compound found in plants like grapes and berries, is gaining recognition for its potent anti-cancer, anti-inflammatory, and antioxidant properties. This review offers a comprehensive examination of resveratrol’s role in cancer prevention and treatment, focusing on its ability to modulate key signaling pathways such as NF-κB, PI3K/Akt, and apoptotic regulators. Resveratrol also reduces oxidative stress by scavenging reactive oxygen species (ROS), contributing to its therapeutic potential. Despite its promise, challenges related to resveratrol’s absorption, distribution, metabolism, and excretion (ADME) limit its clinical application. Recent advancements in drug delivery systems, including liposomes and nanoparticles, have shown potential to improve its bioavailability and therapeutic efficacy. This review also addresses the compound’s safety, toxicity profiles, and interactions with other cancer therapies. Preclinical studies reveal resveratrol’s preventive efficacy, with findings suggesting reductions in the risk of breast and colon cancers by 60–80% through inhibition of precancerous lesions. Additionally, emerging research highlights resveratrol’s synergistic effects when used alongside chemotherapy and radiotherapy, enhancing treatment outcomes. Future research should prioritize large-scale clinical trials to optimize dosage, evaluate the long-term safety, and explore innovative delivery methods to realize resveratrol’s therapeutic potential in cancer carefully. Resveratrol stands as a promising agent in cancer prevention and treatment, warranting further investigation into its clinical applications.

Keywords: Resveratrol, cancer prevention, apoptosis, bioavailability, signaling pathways.

References

Aggarwal, B. B., Bhardwaj, A., Aggarwal, R. S., Seeram, N. P., Shishodia, S., & Takada, Y. (2004). Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies. PubMed, 24(5A), 2783–2840. https://pubmed.ncbi.nlm.nih.gov/15517885

Aggarwal, B. B., Bhardwaj, A., Aggarwal, R. S., Seeram, N. P., Shishodia, S., & Takada, Y. (2004, September 1). Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies. Anticancer Research. https://ar.iiarjournals.org/content/24/5A/2783.short

Almatroodi, S. A., Alsahli, M. A., Aljohani, A. S. M., Alhumaydhi, F. A., Babiker, A. Y., Khan, A. A., & Rahmani, A. H. (2022). Potential therapeutic targets of resveratrol, a plant polyphenol, and its role in the therapy of various types of cancer. Molecules, 27(9), 2665. https://doi.org/10.3390/molecules27092665

Anwar, M. J., Altaf, A., Imran, M., Amir, M., Alsagaby, S. A., Abdulmonem, W. A., Mujtaba, A., El-Ghorab, A. H., Ghoneim, M. M., Hussain, M., Jbawi, E. A., Shaker, M. E., & Abdelgawad, M. A. (2023). Anti-cancer perspectives of resveratrol: A comprehensive review. Food and Agricultural Immunology, 34(1). https://doi.org/10.1080/09540105.2023.2265686

Athar, M., Back, J. H., Tang, X., Kim, K. H., Kopelovich, L., Bickers, D. R., & Kim, A. L. (2007). Resveratrol: A review of preclinical studies for human cancer prevention. Toxicology and Applied Pharmacology, 224(3), 274–283. https://doi.org/10.1016/j.taap.2006.12.025

Athar, M., Back, J. H., Tang, X., Kim, K. H., Kopelovich, L., Bickers, D. R., & Kim, A. L. (2007). Resveratrol: A review of preclinical studies for human cancer prevention. Toxicology and Applied Pharmacology, 224(3), 274–283. https://doi.org/10.1016/j.taap.2006.12.025

Aziz, M., Kumar, R., & Ahmad, N. (2003). Cancer chemoprevention by resveratrol: In vitro and in vivo studies and the underlying mechanisms (review). International Journal of Oncology. https://doi.org/10.3892/ijo.23.1.17

Bala, S., Misra, A., Kaur, U., & Chakrabarti, S. S. (2023). Resveratrol: A novel drug for the management of neurodegenerative disorders. BENTHAM SCIENCE PUBLISHERS eBooks, 230–251. https://doi.org/10.2174/9789815040197123010015

Baur, J. A., & Sinclair, D. A. (2006). Therapeutic potential of resveratrol: The in vivo evidence. Nature Reviews Drug Discovery, 5(6), 493–506. https://doi.org/10.1038/nrd2060

Baur, J. A., & Sinclair, D. A. (2006). Therapeutic potential of resveratrol: The in vivo evidence. Nature Reviews Drug Discovery, 5(6), 493–506. https://doi.org/10.1038/nrd2060

Cai, Y. (2011). Expression of MET and SOX2 genes in non-small cell lung carcinoma with EGFR mutation. Oncology Reports. https://doi.org/10.3892/or.2011.1349

Cheng, K., Song, Z., Zhang, H., Li, S., Wang, C., Zhang, L., & Wang, T. (2019). The therapeutic effects of resveratrol on hepatic steatosis in high-fat diet-induced obese mice by improving oxidative stress, inflammation and lipid-related gene transcriptional expression. Medical Molecular Morphology, 52(4), 187–197. https://doi.org/10.1007/s00795-019-00216-7

Chow, H. S., Garland, L. L., Hsu, C., Vining, D. R., Chew, W. M., Miller, J. A., Perloff, M., Crowell, J. A., & Alberts, D. S. (2010). Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prevention Research, 3(9), 1168–1175. https://doi.org/10.1158/1940-6207.capr-09-0155

Delmas, D., Jannin, B., & Latruffe, N. (2005). Resveratrol: Preventing properties against vascular alterations and ageing. Molecular Nutrition & Food Research, 49(5), 377–395. https://doi.org/10.1002/mnfr.200400098

Du, Q., Hu, B., An, H., Shen, K., Xu, L., Deng, S., & Wei, M. (2013). Synergistic anticancer effects of curcumin and resveratrol in Hepa1-6 hepatocellular carcinoma cells. Oncology Reports, 29(5), 1851–1858. https://doi.org/10.3892/or.2013.2310

El-Readi, M. Z., Eid, S., Abdelghany, A. A., Al-Amoudi, H. S., Efferth, T., & Wink, M. (2019). Resveratrol mediated cancer cell apoptosis, and modulation of multidrug resistance proteins and metabolic enzymes. Phytomedicine, 55, 269–281. https://doi.org/10.1016/j.phymed.2018.06.046

Flourakis, M., Lehen’kyi, V., Beck, B., Raphaël, M., Vandenberghe, M., Abeele, F. V., Roudbaraki, M., Lepage, G., Mauroy, B., Romanin, C., Shuba, Y., Skryma, R., & Prevarskaya, N. (2010). Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells. Cell Death and Disease, 1(9), e75. https://doi.org/10.1038/cddis.2010.52

Froján, D. (2012). Resveratrol in the primary prevention of cardiovascular disease. Cardiovascular Therapeutics, 30(5), e59–e68. https://doi.org/10.1111/j.1755-5922.2011.00292.x

Fukuoka, N., Ishida, T., Ishii, K., Sato, A., Dagli, M. L. Z., Virgona, N., & Yano, T. (2023). Resveratrol can induce differentiating phenotypes in canine oral mucosal melanoma cells. Journal of Veterinary Medical Science, 85(7), 721–726. https://doi.org/10.1292/jvms.22-0446

Fulda, S. (2010). Resveratrol and derivatives for the prevention and treatment of cancer. Drug Discovery Today, 15(17–18), 757–765. https://doi.org/10.1016/j.drudis.2010.07.005

Fulda, S. (2010). Resveratrol and derivatives for the prevention and treatment of cancer. Drug Discovery Today, 15(17–18), 757–765. https://doi.org/10.1016/j.drudis.2010.07.005

Fulda, S., & Debatin, K. (2005). Resveratrol-mediated sensitisation to TRAIL-induced apoptosis depends on death receptor and mitochondrial signalling. European Journal of Cancer, 41(5), 786–798. https://doi.org/10.1016/j.ejca.2004.12.020

Harper, C. E., Patel, B. B., Wang, J., Arabshahi, A., Eltoum, I. A., & Lamartiniere, C. A. (2007). Resveratrol suppresses prostate cancer progression in transgenic mice. Carcinogenesis, 28(9), 1946–1953. https://doi.org/10.1093/carcin/bgm144

Hirota, K., Nakamura, H., Masutani, H., & Yodoi, J. (2002). Thioredoxin superfamily and thioredoxin-inducing agents. Annals of the New York Academy of Sciences, 957(1), 189–199. https://doi.org/10.1111/j.1749-6632.2002.tb02916.x

Hsieh, T., & Wu, J. M. (1999). Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines. Experimental Cell Research, 249(1), 109–115. https://doi.org/10.1006/excr.1999.4471

Islam, F., Shehzadi, U., Saeed, F., Ahmad, R. S., Arshad, M. U., Naseer, M. S., Tariq, F., Ali, R., Khurshid, S., Hussain, G., Ahmad, A., Afzaal, M., Akram, R., Agar, O. T., Imran, A., & Suleria, H. A. (2024). Resveratrol synthesis, metabolism, and delivery: A mechanistic treatise. IntechOpen eBooks. https://doi.org/10.5772/intechopen.114982

J, M., Gj, L., Jy, S., L, C., Ah, W., Xx, G., & Zj, W. (2019). Preliminary results indicate resveratrol affects proliferation and apoptosis of leukemia cells by regulating PTEN/PI3K/AKT pathway. PubMed, 23(10), 4285–4292. https://doi.org/10.26355/eurrev_201905_17933

Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W. W., Fong, H. H. S., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C., & Pezzuto, J. M. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275(5297), 218–220. https://doi.org/10.1126/science.275.5297.218

Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W. W., Fong, H. H. S., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C., & Pezzuto, J. M. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275(5297), 218–220. https://doi.org/10.1126/science.275.5297.218

Jeong, H., Lee, S., Lee, H., Kim, H., Vuong, T. A., Cho, H., Bae, G., & Kang, J. (2019). Prmt7 promotes myoblast differentiation via methylation of p38MAPK on arginine residue 70. Cell Death and Differentiation, 27(2), 573–586. https://doi.org/10.1038/s41418-019-0373-y

Jo, W. S., Kim, S. D., Jeong, S. K., Oh, S. J., Park, M. T., Lee, C. G., Kang, Y. R., & Jeong, M. H. (2022). Resveratrol analogue, HS-1793, inhibits inflammatory mediator release from macrophages by interfering with the TLR4-mediated NF-κB activation. Food Science and Biotechnology, 31(4), 433–441. https://doi.org/10.1007/s10068-022-01052-9

Kalantari, S., Xu, T. B., Mostafavi, A., Lee, A., Barankevich, R., Boot, W. R., & Czaja, S. J. (2022). Using a nature-based virtual reality environment for improving mood states and cognitive engagement in older adults: A mixed-method feasibility study. Innovation in Aging, 6(3). https://doi.org/10.1093/geroni/igac015

Kar, A., Rashid, M. H. O., Sunny, A. R., Raposo, A., Islam, M. S., Hussain, M. A., ... & Rahman, M. M. (2024). Diagnostic efficacy of tumor biomarkers AFP, CA19-9, and CEA in hepatocellular carcinoma patients. Journal of Angiotherapy, 8(4), 9513.

Kim, D. H., Kim, M. J., Sung, B., Suh, H., Jung, J. H., Chung, H. Y., & Kim, N. D. (2016). Resveratrol analogue, HS-1793, induces apoptotic cell death and cell cycle arrest through downregulation of AKT in human colon cancer cells. Oncology Reports, 37(1), 281–288. https://doi.org/10.3892/or.2016.5219

Kiskova, T., Kubatka, P., Büsselberg, D., & Kassayova, M. (2020). The plant-derived compound resveratrol in brain cancer: A review. Biomolecules, 10(1), 161. https://doi.org/10.3390/biom10010161

Ko, J., Sethi, G., Um, J., Shanmugam, M. K., Arfuso, F., Kumar, A. P., Bishayee, A., & Ahn, K. S. (2017). The role of resveratrol in cancer therapy. International Journal of Molecular Sciences, 18(12), 2589. https://doi.org/10.3390/ijms18122589

Komorowska, D., Radzik, T., Kalenik, S., & Rodacka, A. (2022). Natural radiosensitizers in radiotherapy: Cancer treatment by combining ionizing radiation with resveratrol. International Journal of Molecular Sciences, 23(18), 10627. https://doi.org/10.3390/ijms231810627

Koushki, M., Amiri-Dashatan, N., Ahmadi, N., Abbaszadeh, H., & Rezaei-Tavirani, M. (2018). Resveratrol: A miraculous natural compound for diseases treatment. Food Science & Nutrition, 6(8), 2473–2490. https://doi.org/10.1002/fsn3.855

Kumar, A., Kurmi, B. D., Singh, A., & Singh, D. (2022). Potential role of resveratrol and its nano-formulation as anti-cancer agent. Exploration of Targeted Anti-tumor Therapy, 643–658. https://doi.org/10.37349/etat.2022.00105

Kursvietiene, L., Kopustinskiene, D. M., Staneviciene, I., Mongirdiene, A., Kubová, K., Masteikova, R., & Bernatoniene, J. (2023). Anti-cancer properties of resveratrol: A focus on its impact on mitochondrial functions. Antioxidants, 12(12), 2056. https://doi.org/10.3390/antiox12122056

Lee, I., Park, C., & Kang, W. K. (2010). Knockdown of inwardly rectifying potassium channel KIR2.2 suppresses tumorigenesis by inducing reactive oxygen species-mediated cellular senescence. Molecular Cancer Therapeutics, 9(11), 2951–2959. https://doi.org/10.1158/1535-7163.mct-10-0511

Leonard, S. S., Xia, C., Jiang, B., Stinefelt, B., Klandorf, H., Harris, G. K., & Shi, X. (2003). Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochemical and Biophysical Research Communications, 309(4), 1017–1026. https://doi.org/10.1016/j.bbrc.2003.08.105

Malviya, V., Tawar, M., Burange, P., & Jodh, R. (2022). A brief review on resveratrol. Asian Journal of Research in Pharmaceutical Sciences, 157–162. https://doi.org/10.52711/2231-5659.2022.00027

Montalesi, E., Cracco, P., Acconcia, F., Fiocchetti, M., Iucci, G., Battocchio, C., Orlandini, E., Ciccone, L., Nencetti, S., Muzzi, M., Moreno, S., Venditti, I., & Marino, M. (2023). Resveratrol analogs and prodrugs differently affect the survival of breast cancer cells impairing estrogen/estrogen receptor α/neuroglobin pathway. International Journal of Molecular Sciences, 24(3), 2148. https://doi.org/10.3390/ijms24032148

Nguyen, A. V., Martínez, M., Stamos, M. J., Moyer, M. P., Planutis, K., & Holcombe, R. F. (2009). Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Management and Research, 1, 25–37. https://doi.org/10.2147/cmar.s4335

Patel, K. R., Scott, E., Brown, V. A., Gescher, A. J., Steward, W. P., & Brown, K. (2011). Clinical trials of resveratrol. Annals of the New York Academy of Sciences, 1215(1), 161–169. https://doi.org/10.1111/j.1749-6632.2010.05853.x

Popat, R., Plesner, T., Davies, F., Cook, G., Cook, M., Elliott, P., Jacobson, E., Gumbleton, T., Oakervee, H., & Cavenagh, J. (2012). A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. British Journal of Haematology, 160(5), 714–717. https://doi.org/10.1111/bjh.12154

Retraction. (2021). Journal of Cellular Biochemistry, 122(S1). https://doi.org/10.1002/jcb.29984

Rizzo, P., Osipo, C., Foreman, K., Golde, T., Osborne, B., & Miele, L. (2008). Rational targeting of Notch signaling in cancer. Oncogene, 27(38), 5124–5131. https://doi.org/10.1038/onc.2008.226

Sabra, A., Netticadan, T., & Wijekoon, C. (2021). Grape bioactive molecules, and the potential health benefits in reducing the risk of heart diseases. Food Chemistry X, 12, 100149. https://doi.org/10.1016/j.fochx.2021.100149

Sajadimajd, S., Aghaz, F., Khazaei, M., & Raygani, A. (2023). The anti-cancer effect of resveratrol nano-encapsulated supplements against breast cancer via the regulation of oxidative stress. Journal of Microencapsulation, 40(5), 318–329. https://doi.org/10.1080/02652048.2023.2198026

Scarlatti, F., Sala, G., Somenzi, G., Signorelli, P., Sacchi, N., & Ghidoni, R. (2003). Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. The FASEB Journal, 17(15), 2339–2341. https://doi.org/10.1096/fj.03-0292fje

Sheth, S., Jajoo, S., Kaur, T., Mukherjea, D., Sheehan, K., Rybak, L. P., & Ramkumar, V. (2012). Resveratrol reduces prostate cancer growth and metastasis by inhibiting the AKT/MicroRNA-21 pathway. PLoS ONE, 7(12), e51655. https://doi.org/10.1371/journal.pone.0051655

Shukla, Y., & Singh, R. (2011). Resveratrol and cellular mechanisms of cancer prevention. Annals of the New York Academy of Sciences, 1215(1), 1–8. https://doi.org/10.1111/j.1749-6632.2010.05870.x

Singh, K. B., Ji, X., & Singh, S. V. (2018). Therapeutic potential of leelamine, a novel inhibitor of androgen receptor and castration-resistant prostate cancer. Molecular Cancer Therapeutics, 17(10), 2079–2090. https://doi.org/10.1158/1535-7163.mct-18-0117

Sun, H., Cai, H., Fu, Y., Wang, Q., Ji, K., Du, L., Xu, C., Tian, L., He, N., Wang, J., Zhang, M., Liu, Y., Wang, Y., Li, J., & Liu, Q. (2020). The protection effect of resveratrol against radiation-induced inflammatory bowel disease via NLRP-3 inflammasome repression in mice. Dose-Response, 18(2), 155932582093129. https://doi.org/10.1177/1559325820931292

Tseng, S., Lin, S., Chen, J., Su, Y., Huang, H., Chen, C., Lin, P., & Chen, Y. (2004). Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clinical Cancer Research, 10(6), 2190–2202. https://doi.org/10.1158/1078-0432.ccr-03-0105

Tufael, M. M. R., Kar, A., Upadhye, V. J., & others. (2024). Serum biomarkers' significance and gender-specific hepatocellular carcinoma insights of fisher patients in Bangladesh. Journal of Angiotherapy, 8(1), 1–9, 9440.

Tufael, M. M. R., Rahman, M., Upadhye, V. J., Kar, A., & others. (2024). Combined biomarkers for early diagnosis of hepatocellular carcinoma. Journal of Angiotherapy, 8(5), 1–12, 9665.

Van Ginkel, P. R., Sareen, D., Subramanian, L., Walker, Q., Darjatmoko, S. R., Lindstrom, M. J., Kulkarni, A., Albert, D. M., & Polans, A. S. (2007). Resveratrol inhibits tumor growth of human neuroblastoma and mediates apoptosis by directly targeting mitochondria. Clinical Cancer Research, 13(17), 5162–5169. https://doi.org/10.1158/1078-0432.ccr-07-0347

Vanamala, J., Reddivari, L., Radhakrishnan, S., & Tarver, C. (2010). Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer, 10(1). https://doi.org/10.1186/1471-2407-10-238

Wei, R., Yang, L., Ren, H., Wang, P., Liu, X., Luo, Y., & Li, S. (2016). Zinc sulfide nanospheres prepared by a solvothermal method for selective fluorescence detection of glutathione. Analytical Methods, 8(26), 5381–5388. https://doi.org/10.1039/c6ay00925a

Xiao, Q., Zhu, W., Feng, W., Lee, S. S., Leung, A. W., Shen, J., Gao, L., & Xu, C. (2019). A review of resveratrol as a potent chemoprotective and synergistic agent in cancer chemotherapy. Frontiers in Pharmacology, 9. https://doi.org/10.3389/fphar.2018.01534

Xie, C., Liang, C., Wang, R., Yi, K., Zhou, X., Li, X., Chen, Y., Miao, D., Zhong, C., & Zhu, J. (2023). Resveratrol suppresses lung cancer by targeting cancer stem-like cells and regulating tumor microenvironment. The Journal of Nutritional Biochemistry, 112, 109211. https://doi.org/10.1016/j.jnutbio.2022.109211

Zhang, X., Zhang, S., Yin, Q., & Zhang, J. (2015). Quercetin induces human colon cancer cells apoptosis by inhibiting the nuclear factor-kappa B pathway. Pharmacognosy Magazine, 11(42), 404. https://doi.org/10.4103/0973-1296.153096