Int. J. Mol. Sci. 2016, 17(6), 973; https://doi.org/10.3390/ijms17060973
Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism
Haseeb Zubair 1,2, Shafquat Azim 1,2, Husain Yar Khan 1,3, Mohammad Fahad Ullah 1,4, Daocheng Wu 5, Ajay Pratap Singh 2, Sheikh Mumtaz Hadi 1,*
and Aamir Ahmad 2,*
1
Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh 202002, India
2
Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
3
UoN Chair of Oman’s Medicinal Plants and Marine Natural Products, University of Nizwa, Birkat Al Mauz, PO Box 33, 616 Nizwa, Oman
4
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
5
Key Laboratory of Biomedical Information Engineering of Education Ministry, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710048, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Sotiris Hadjikakou
Received: 28 April 2016 / Revised: 7 June 2016 / Accepted: 14 June 2016 / Published: 20 June 2016
(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)
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. View Full-TextKeywords:
gossypol; apogossypolone (ApoG2); copper; prooxidant; anticancer
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Zubair, H.; Azim, S.; Khan, H.Y.; Ullah, M.F.; Wu, D.; Singh, A.P.; Hadi, S.M.; Ahmad, A. Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism. Int. J. Mol. Sci. 2016, 17, 973.
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