Copper Signaling Axis as a Target for Prostate Cancer Therapeutics

Abstract

Previously published reports indicate that serum copper levels are elevated in prostate cancer (PCa) patients and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for PCa cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting PCa cell proclivity for copper uptake, we developed a “conditional lethal” screen to identify compounds whose cytotoxic actions were manifest in a copper-dependent manner. Emerging from this screen were a series of dithiocarbamates, which when complexed with copper, induced Reactive Oxygen Species (ROS)-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, Disulfiram (DSF), is an FDA approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies DSF alone had a minimal effect on the growth of PCa tumors when propagated as xenografts. However, when DSF was coadministered with copper a very dramatic inhibition of tumor growth in models of hormone sensitive and of castrate resistant disease was observed. Furthermore, we determined that prostate cancer (PCa) cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of AR-positive PCa cell lines with androgens. Not surprisingly robust CTR1-dependent uptake of copper into PCa cells was observed; an activity that was accentuated by activation of androgen receptor (AR). Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of PCa patients whose disease is resistant to classical androgen ablation therapies.

Cuprous oxide nanoparticles inhibit prostate cancer by attenuating the stemness of cancer cells via inhibition of the Wnt signaling pathway

“…15,16 As CRPC is one of the possible manifestations of ADT during prostate cancer treatment and the overall survival benefit of marketed drugs is limited, it is necessary to explore the pharmacological effects of CONPs on CRPC. In addition, our previous study shows that melanoma is highly sensitive to CONPs 15,16 and that melanoma and prostate cancer exhibit similar copper metabolism disorder characteristics, [17][18][19] which suggests that CONPs may also affect prostate cancer, including CRPC.…”

Copper signaling in the brain and beyond

“…As a result, substantial research has been dedicated to understanding and manipulating copper in cancer to prevent cancer progression. Delivery of copper to cancer cells, for example as a disulfiram complex (74) or bis(thiosemicarbazonato) complex (eg. Cu(gtsm) (75)), takes advantage of the oxidizing environment in cancer cells, which is less equipped to buffer increases in copper, to cause cell death (76).…”

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

“…DSF is available, inexpensive, safe, and overall well-tolerated making it an attractive candidate for "repurposing" in the context of glioblastoma. Although the anticancer mechanisms of DSF are still not well-understood (22), published data indicate that the cytotoxicity of DSF is enhanced in the presence of copper (14,15,23). DSF chelates bivalent metals such as copper (Cu) and zinc (Zn) to form DSF metal complexes that inhibit proteasome activity and block the degradation of IkB and NFkB nuclear translocation (24)(25)(26).…”