Resveratrol, cancer and cancer stem cells: A review on past to future Vasanth K. Bhaskara a , Bharti Mittal b , Vijaya V. Mysorekar c , Nagarathna Amaresh d , Jesus Simal-Gandara e, * a Department of Biochemistry-PG, Ramaiah Post Graduate Center, Ramaiah College - RCASC, Bengaluru 560054, India b Immuniteit Lab Pvt Ltd., Electronic City, Bengaluru 560024, India c Department of Pathology, Ramaiah Medical College & Hospitals (RMCH), Bengaluru 560054, India d Department of Biotechnology, Ramaiah Post Graduate Center, Ramaiah College – RCASC, Bengaluru 560054, India e Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo – Ourense Campus, E32004 Ourense, Spain ARTICLE INFO Keywords: Resveratrol Cancer Cancer stem cells Therapeutic targeting Signal transduction Resistance In vitro and in vivo studies ABSTRACT Cancer remains to be an unresolved medical challenge despite of tremendous advancement in basic science research and clinical medicine. One of the major limitations is due to the side effects of chemotherapy which remains to be palliative without offering any permanent cure for cancer. Cancer stem cells (CSCs) are the sub- population of cells in tumors that remain viable even after surgery, chemo- and radio-therapy that eventually responsible for tumor relapse. Hence, by eliminating non-stem cancer cells and cancer stem cells from the patient, permanent cure is expected. Phytochemicals have been under the intensive study to target these CSCs effectively and permanently as they do not cause any side effects. Resveratrol (RSV) is one such compound attaining lot of interest in recent days to target CSCs either alone or in combination. RSV has been used by several researchers to target cancer cells in a variety of disease models, however its CSC targeting abilities are under intensive study at present. This review is to summarize the effects of RSV under in vitro and in vivo conditions along with advantages and disadvantages of its uses against cancer cells and cancer stem cells. From the first reports on phytochemical applications against cancer and cancer stem cells in 1997 and 2002 respectively followed by later reports, up to date observations and developments are enlisted from PubMed in this comprehensive review. RSV is shown to be a potential compound having impact on altering the signal transduction pathways in cancer cells. However, the effects are variable under in vitro and in vivo conditions, and also with its use alone or in combination with other small molecules. Past research on RSV is emphasizing the importance of in vivo experimental models and clinical trials with different prospective combinations, is a hope for future promising treatment regimen. 1. Introduction Resveratrol (RSV), is 3,4’,5 – trihydroxy stilbene, a phytoalexin is widely distributed in variety of plants including red grapes, berries, peanuts, etc. Highest levels of RSV are found in Japanese knotweed (Polygonum cuspidatum) and muscadine grapes (Vitis rotundifolia)(Shri- kanta et al., 2015). Though its occurrence is widely distributed about more than 70 plant species, its bioavailability is challenging upon its consumption (Gambini et al., 2015). Tome-Carneiro et al. (2013) have further shown, different levels of RSV concentrations are attributed for differential health impacts. Szekeres et al. (2010) in their review demonstrated that, due to the presence of three hydroxyl groups, it was known to act as a potent anti-oxidant by interfering with intracellular redox signaling. In many studies with different model organisms, RSV is shown to increase healthy life span mediated by SIRT1 (NAD-dependent deacetylase sirtuin-1) (Bhullar and Hubbard, 2015). RSV can reduce in- flammatory stress through its effects on mitochondria. It activates a group of mitochondrial proteins of sirtuin family, particularly SIRT1. Lagouge et al. (2006) had shown that activation of sirtuin family protein can in turn related to the blood sugar stabilization in the body. RSV effects on nitric oxide cycle were well known, through which it maintains the health of immune, nervous and vascular system. Nitric oxide in the body is synthesized by the enzyme Nitric Oxide Synthase (NOS) which has a critical role in inflammation. NOS can occur in * Corresponding author. E-mail addresses: vasanthkbhaskara@gmail.com (V.K. Bhaskara), genomicsbioinformatics2976@gmail.com (B. Mittal), vijayamysorekar1@gmail.com (V.V. Mysorekar), dr.nagarathnaa@gmail.com (N. Amaresh), jsimal@uvigo.es (J. Simal-Gandara). Contents lists available at ScienceDirect Current Research in Food Science journal homepage: www.editorialmanager.com/crfs/ https://doi.org/10.1016/j.crfs.2020.10.004 Received 15 August 2020; Received in revised form 28 October 2020; Accepted 29 October 2020 2665-9271/© 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Current Research in Food Science 3 (2020) 284–295