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.
International journal of molecular sciences. 2016 Jun 20*** epublish ***
Haseeb Zubair, Shafquat Azim, Husain Yar Khan, Mohammad Fahad Ullah, Daocheng Wu, Ajay Pratap Singh, Sheikh Mumtaz Hadi, Aamir Ahmad
Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. ., Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. ., Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. ., Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. ., Key Laboratory of Biomedical Information Engineering of Education Ministry, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710048, China. ., Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA. ., Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India. ., Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA. .