title: Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism.
abstract: There is compelling evidence that serum, tissue and intracellular levels of copper are elevated in all types of cancer. Copper has been suggested as an important co-factor for angiogenesis. It is also a major metal ion present inside the nucleus, bound to DNA bases, particularly guanine. We have earlier proposed that the interaction of phenolic-antioxidants with intracellular copper leads to the generation of reactive oxygen species (ROS) that ultimately serve as DNA cleaving agents. To further validate our hypothesis we show here that the antioxidant gossypol and its semi-synthetic derivative apogossypolone induce copper-mediated apoptosis in breast MDA-MB-231, prostate PC3 and pancreatic BxPC-3 cancer cells, through the generation of ROS. MCF10A breast epithelial cells refractory to the cytotoxic property of these compounds become sensitized to treatment against gossypol, as well as apogossypolone, when pre-incubated with copper. Our present results confirm our earlier findings and strengthen our hypothesis that plant-derived antioxidants mobilize intracellular copper instigating ROS-mediated cellular DNA breakage. As cancer cells exist under significant oxidative stress, this increase in ROS-stress to cytotoxic levels could be a successful anticancer approach.
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. hzubair@health.southalabama.edu.|Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA. hzubair@health.southalabama.edu.
authors.forename: Haseeb
authors.initials: H
authors.lastname: Zubair
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. SAzim@health.southalabama.edu.|Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA. SAzim@health.southalabama.edu.
authors.forename: Shafquat
authors.initials: S
authors.lastname: Azim
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. husainyar@gmail.com.|UoN Chair of Oman's Medicinal Plants and Marine Natural Products, University of Nizwa, Birkat Al Mauz, PO Box 33, 616 Nizwa, Oman. husainyar@gmail.com.
authors.forename: Husain Yar
authors.initials: HY
authors.lastname: Khan
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. m.ullah@ut.edu.sa.|Prince Fahad Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, P.O. Box 741, Tabuk-71491, Saudi Arabia. m.ullah@ut.edu.sa.
authors.forename: Mohammad Fahad
authors.initials: MF
authors.lastname: Ullah
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Education Ministry, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710048, China. wudaocheng@mail.xjtu.edu.cn.
authors.forename: Daocheng
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA. asingh@health.southalabama.edu.
authors.forename: Ajay Pratap
authors.initials: AP
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. smhadi1946@gmail.com.
authors.forename: Sheikh Mumtaz
authors.initials: SM
authors.lastname: Hadi
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA. aahmad@health.southalabama.edu.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism*; D004249:DNA Damage; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; C534401:apogossypolone; D003300:Copper; D006072:Gossypol
keywords: anticancer; apogossypolone (ApoG2); copper; gossypol; prooxidant