title: Resveratrol-induced apoptosis is enhanced in low pH environments associated with cancer.
abstract: Many critical factors such as hypoxia, nutrient deficiency, activation of glycolytic pathway/Warburg effect contribute to the observed low pH in tumors compared to normal tissue. Studies suggest that such tumor specific acidic environment can be exploited for the development of therapeutic strategies against cancer. Independent observations show reduction in pH of mammalian cells undergoing internucleosomal DNA fragmentation and apoptosis. As such, our group has extensively demonstrated that anticancer mechanisms of different plant polyphenols involve mobilization of endogenous copper and consequent internucleosomal DNA breakage. Copper is redox active metal, an essential component of chromatin and is sensitive to subtle pH changes in its microenvironment. Here we explored whether, acidic pH promotes growth inhibition, apoptosis, and DNA damaging capacity of chemopreventive agent resveratrol. Our results reveal that growth inhibition and internucleosomal DNA fragmentation induced apoptosis in Capan-2 and Panc-28 pancreatic cancer cell lines (and not in normal HPDE cells) by resveratrol is enhanced at lower pH. Using comet assay, we further demonstrate that DNA breakage by resveratrol is enhanced with acidification. Membrane permeable copper specific chelator neocuproine (and not iron chelator orthophenanthroline) abrogated growth inhibition and apoptosis by resveratrol. Western blot results show enhanced activation of DNA laddering marker H2.aX by resveratrol at acidic pH that was reversed by neocuproine and not by orthophenanthroline. Our findings provide irrevocable proof that low pH environment can be turned into tumor weakness and assist in eradication of cancer cells by resveratrol.
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, UP, India.
authors.forename: Uzma
authors.initials: U
authors.lastname: Shamim
authors.forename: Sarmad
authors.initials: S
authors.lastname: Hanif
authors.forename: Abdulmajeed
authors.initials: A
authors.lastname: Albanyan
authors.forename: Frances W J
authors.initials: FW
authors.lastname: Beck
authors.forename: Bin
authors.initials: B
authors.lastname: Bao
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
authors.forename: Sheikh M
authors.initials: SM
authors.lastname: Hadi
authors.forename: Asfar S
authors.initials: AS
authors.lastname: Azmi
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D004249:DNA Damage; D053938:DNA Fragmentation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D059016:Tumor Microenvironment
chemical_list: D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D002614:Chelating Agents; C468783:H2AX protein, human; D006657:Histones; D013267:Stilbenes; D003300:Copper; D000077185:Resveratrol