The Complex of Copper (II) and Zoledronic Acid: Relevance to Oxidative Death of Leukemia Cells in the Bone Marrow

Copper-organic compounds are being investigated as antitumor candidates. Besides their efficacy as cytotoxic agents alone, the oxidative potential of electrochemical Cu²⁺-to-Cu¹⁺ transition emerges as an attractive approach for elimination of tumor cells otherwise resistant to chemotherapy. To minimize side effects of the potent oxidative burst upon Cu(II) reduction, the metal cations should be delivered to the tumor site. Taking advantage of the ability of bisphosphonates to accumulate in the bone, we synthesized a Cu(II) complex of zoledronic acid (ZA), an FDA-approved drug for prevention of bone destruction. The <b>CuZA</b> complex obtained upon precipitation of ZA and different copper salts (sulfate, chloride or perchlorate) were structurally identical, consisting of two organic moieties coordinated by three metal cations. Combined treatment with water-soluble formulations of <b>CuZA</b> and cysteine triggered rapid death in human cell lines. This effect was achievable with non-toxic concentrations of <b>CuZA</b> and cysteine alone. Importantly, the K562 chronic myelogenous leukemia cells that demonstrated an attenuated response to the 3d generation Bcr-Abl tyrosine kinase inhibitor in the medium conditioned by bone marrow-derived fibroblasts, were readily killed by <b>CuZA</b>-cysteine combination. Thus, oxidative burst upon metal reduction in <b>CuZA</b> complexes emerges as a promising method of eradication of tumor cells in the bone microenvironment.