Apogossypolone, derivative of gossypol, mobilizes endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage
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- 作者：Haseeb Zubair ; Husain Y. Khan ; M.F. Ullah ; Aamir Ahmad ; Daocheng Wu ; S.M. Hadi
- 关键词：ApoG2 ; apogossypolone
- 刊名：European Journal of Pharmaceutical Sciences
- 出版年：2012
- 出版时间：30 August, 2012
- 年：2012
- 卷：47
- 期：1
- 页码：280-286
- 全文大小：550 K
文摘
Gossypol is a polyphenolic aldehyde that is produced in the cotton plant. Since long it has been reported to possess antiproliferative activity against a variety of cancer cell lines as well as tumor regression in animal models. However, the toxicity of gossypol does not permit it to be an effective antitumor agent. One of the derivatives of gossypol to show promising results is apogossypolone. For example, it has been shown to specifically target tumor growth in hepatocellular carcinoma xenograft in nude mice without causing any damage to normal tissue. Using human peripheral lymphocytes, in this paper we show that both gossypol and its semi-synthetic derivative apogossypolone cause oxidative DNA breakage in these cells through the mobilization of endogenous copper ions. Such cellular DNA breakage is inhibited by copper specific chelator but nor by iron or zinc chelating agents. Similar results are obtained with isolated nuclei indicating that chromatin bound copper is mobilized in this reaction. Further, apogossypolone showed enhanced DNA breakage and increased oxidative stress in whole lymphocytes as compared with gossypol indicating that this is possibly the result of greater permeability of apogossypolone. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Therefore, cancer cells may be subject to greater electron transfer between copper ions and gossypol/apogossypolone to generate reactive oxygen species responsible for DNA cleavage. This may account for the preferential cytotoxicity of apogossypolone towards tumor cells.