Copper Chelation by D-penicillamine Generates Reactive Oxygen Species that are Cytotoxic to Human Leukemia and Breast Cancer Cells

Gupte A, Mumper RJ. Free Radical Biology & Medicine.  (2007) 43:1271-1278

Department of Pharmaceutical Sciences, College of Pharmacy, University of
Kentucky, Lexington, KY 40536-0082, USA.

Serum and tumor copper levels are significantly elevated in a variety of alignancies including breast, ovarian, gastric, lung, and leukemia. D-Penicillamine (D-pen), a copper-chelating agent, at low concentrations in the
presence of copper generates concentration-dependent cytotoxic hydrogen peroxide (H(2)O(2)). The purpose of these studies was to investigate the in vitro cytotoxicity, intracellular reactive oxygen species (ROS) generation, and the eduction in intracellular thiol levels due to H(2)O(2) and other ROS generated from copper-catalyzed D-pen oxidation in human breast cancer cells (BT474, MCF-7) and human leukemia cells (HL-60, HL-60/VCR, HL-60/ADR). D-pen (</=400 muM) in the resence of cupric sulfate (10 muM) resulted in concentration-dependent cytotoxicity. Catalase was able to completely protect the cells, substantiating
the involvement of H(2)O(2) in cancer cell cytotoxicity. A linear correlation between the D-pen concentration and the intracellular ROS generated was shown in both breast cancer and leukemia cells. D-pen in the presence of copper also resulted in a reduction in intracellular reduced thiol levels. The H(2)O(2)-mediated cytotoxicity was greater in leukemia cells compared to breast cancer cells. These results support the hypothesis that D-pen can be employed as a cytotoxic copper-chelating agent based on its ROS-generating ability.

PMID: 17893040 [PubMed - in process]