Increasing intracellular bioavailable copper selectively targets prostate cancer cells
Research output: Contribution to journal › Article › Research › peer-review
The therapeutic efficacy of two bis(thiosemicarbazonato) copper complexes, glyoxalbis[N4-methylthiosemicarbazonato]CuII [CuII(gtsm)] and diacetylbis[N4-methylthiosemicarbazonato]CuII [CuII(atsm)], for the treatment of prostate cancer was assessed in cell culture and animal models. Distinctively, copper dissociates intracellularly from CuII(gtsm) but is retained by CuII(atsm). We further demonstrated that intracellular H2gtsm [reduced CuII(gtsm)] continues to redistribute copper into a bioavailable (exchangeable) pool. Both CuII(gtsm) and CuII(atsm) selectively kill transformed (hyperplastic and carcinoma) prostate cell lines but, importantly, do not affect the viability of primary prostate epithelial cells. Increasing extracellular copper concentrations enhanced the therapeutic capacity of both CuII(gtsm) and CuII(atsm), and their ligands (H2gtsm and H2atsm) were toxic only toward cancerous prostate cells when combined with copper. Treatment of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model with CuII(gtsm) (2.5 mg/kg) significantly reduced prostate cancer burden ( approximately 70 ) and severity (grade), while treatment with CuII(atsm) (30 mg/kg) was ineffective at the given dose. However, CuII(gtsm) caused mild kidney toxicity in the mice, associated primarily with interstitial nephritis and luminal distention. Mechanistically, we demonstrated that CuII(gtsm) inhibits proteasomal chymotrypsin-like activity, a feature further established as being common to copper-ionophores that increase intracellular bioavailable copper. We have demonstrated that increasing intracellular bioavailable copper can selectively kill cancerous prostate cells in vitro and in vivo and have revealed the potential for bis(thiosemicarbazone) copper complexes to be developed as therapeutics for prostate cancer.