Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism.

Haseeb Zubair,Daocheng Wu,Shafquat Azim,Husain Khan,Mohammad Ullah,Sheikh Hadi,Aamir Ahmad,Ajay Singh

doi:10.3390/ijms17060973

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.

Highlights

Cancer still remains a leading cause of deaths worldwide [1]
We have earlier proposed that the interaction of phenolic-antioxidants with intracellular copper leads to the generation of reactive oxygen species (ROS) that serve as DNA cleaving agents
In view of our findings and those of others in literature we suggest that the antioxidants possessing anticancer and apoptosis inducing activities mobilize copper ions, possibly endogenous chromatin-bound copper, and lead to the generation of reactive oxygen species [19,20]

Summary

Introduction

Cancer still remains a leading cause of deaths worldwide [1]. The development and progression of cancer is a dynamic and long-term process triggered by alterations in genetic sequences and acquiring of specific characteristics that enable development of full malignancy [2]. It has been suggested that even within a single type of tumor, different genomic signatures can be present in different transformed cells [3]. A similar tumor in different individuals tends to have different mutations and genetic structures involved. Despite the complexity of the carcinogenesis process and the different types of mutations, the arising characteristic changes are often a small number of molecular, biochemical, and cellular traits, which often lead to changes in the metabolic status of the tumor as compared to normal cells [5,6,7,8]. Targeting the arising metabolic changes, unique to all types of cancer, rather than the mutations responsible for these metabolic changes can facilitate the development of potential anticancer agents at a faster rate

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Results

Conclusion