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

## TL;DR

A copper complex with zoledronic acid can kill leukemia cells in the bone marrow by triggering oxidative stress.

## Contribution

A new copper-based compound is proposed for targeting leukemia cells in bone marrow with minimal toxicity.

## Key findings

- The CuZA complex combined with cysteine rapidly kills human leukemia cell lines.
- The CuZA–cysteine combination effectively targets K562 leukemia cells resistant to standard drugs.
- The complex shows promise for eradicating tumor cells in the bone microenvironment.

## Abstract

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 CuZA 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 CuZA and cysteine triggered rapid death in human cell lines. This effect was achievable with non-toxic concentrations of CuZA 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 CuZA–cysteine combination. Thus, oxidative burst upon metal reduction in CuZA complexes emerges as a promising method of eradication of tumor cells in the bone microenvironment.