title: Apogossypolone, derivative of gossypol, mobilizes endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage.
abstract: 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.
authors.affiliation: Department of Biochemistry, Aligarh Muslim University, Aligarh 202002, India.
authors.forename: Haseeb
authors.initials: H
authors.lastname: Zubair
authors.forename: Husain Y
authors.initials: HY
authors.lastname: Khan
authors.forename: M F
authors.initials: MF
authors.lastname: Ullah
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Daocheng
authors.initials: D
authors.lastname: Wu
authors.forename: S M
authors.initials: SM
authors.lastname: Hadi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D003300:Copper / Q000097:blood*; D053960:DNA Breaks; D004249:DNA Damage / Q000187:drug effects; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D002843:Chromatin; D017382:Reactive Oxygen Species; C534401:apogossypolone; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron; D015032:Zinc; D006072:Gossypol