Poster Presentation 25th Lorne Cancer Conference 2013

Increasing intracellular bioavailable copper destroys prostate cancer (#137)

Michael A Cater 1 2 3 4 , Helen Pearson 1 2 , Kamil Wolyniec 1 , Paul Klaver 1 , Maree Bilandzic 5 6 , Brett Paterson 7 8 , Ashley Bush 9 , Patrick Humbert 1 2 3 10 , Sharon La Fontaine 6 , Paul Donnelly 7 8 , Ygal Haupt 1 2 3 11
  1. Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
  4. Centre for Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
  5. Prince Henry's Institute, Melbourne, Victoria, Australia
  6. Deakin University, Melbourne, Victoria, Australia
  7. School of Chemistry, University of Melbourne, Melbourne, Victoria, Australia
  8. Bio21 Molecular Sciences and Biotechnology Institute, Melbourne, Victoria, Australia
  9. Mental Health Research Institute, Melbourne, Victoria, Australia
  10. Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia
  11. Department of Biochemistry and Molecular Biology, Monash Univeristy, Melbourne, Victoria, Australia

Elevated intracellular copper levels predispose cancerous cells to ionophoric-copper sensitivity and several classes of copper coordinating lipophilic compounds (hydroxyquinolines, dithiocarbamates and thiosemicarbazones) are being investigated as potential anticancer therapeutics(1-4). Despite reports dating back to the 1970s, which demonstrate that cancerous cells harbor elevated copper(1), there is still insufficient information on how cellular transformation drives copper accumulation, or on the mechanism(s) by which cells adapt to tolerate the ensuing oxidative pressure (not mutually exclusive). Nonetheless, ionophoric-copper therapy may be applicable to a range of cancer types including prostate, breast, ovarian, cervical, lung, stomach, and leukaemia, where copper levels are intrinsically augmented (reviewed in(1)). We assessed the therapeutic efficacy of two bis(thiosemicarbazoneato) copper complexes, glyoxalbis[N(4)-methylthiosemi-carbazonato]CuII [CuII(gtsm)] and diacetylbis[N4-methylthiosemicarbazonato]CuII [CuII(atsm)] for the treatment of prostate cancer. 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 intracellular copper into an exchangeable (bioavailable) pool. Both CuII(gtsm) and CuII(atsm) selectively kill transformed (hyperplastic and carcinoma) prostatic cell lines without affecting the viability of primary prostate epithelial cells. Increasing extracellular copper enhanced their therapeutic capacity and both H2gtsm and H2atsm ligands were only toxic towards cancerous prostate cells when combined with copper. Treatment of the TRAMP mouse model with CuII(gtsm) significantly reduced prostate cancer burden and severity (grade), while treatment with CuII(atsm) was ineffective at the given dose. Finally, 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 provide compelling evidence that increasing intracellular bioavailable copper can selectively kill cancerous prostate cells in vitro and in vivo and reveal the potential for bis(thiosemicarbazone) copper complexes to be developed as therapeutics for prostate cancer.

  1. Gupte, A., and Mumper, R.J. 2009. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treatment Reviews 35:32-46.
  2. Schimmer, A.D., Jitkova, Y., Gronda, M., Wang, Z., Brandwein, J., Chen, C., Gupta, V., Schuh, A., Yee, K., Chen, J., et al. 2012. A Phase I Study of the Metal Ionophore Clioquinol in Patients With Advanced Hematologic Malignancies. Clin Lymphoma Myeloma Leuk: in press.
  3. Lin, J., Haffner, M.C., Zhang, Y., Lee, B.H., NathanielBrennen, W., Britton, J., Kachhap, S.K., Shim, J.S., Liu, J.O., Nelson, W., et al. 2011. Disulfiram Is a DNA Demethylating Agent and Inhibits Prostate Cancer Cell Growth. Prostate 71:333–343.
  4. Bica, L., Meyerowitz, J., Parker, S.J., Caragounis, A., Du, T., Paterson, B.M., Barnham, K.J., Crouch, P.J., White, A.R., and Donnelly, P.S. 2011. Cell cycle arrest in cultured neuroblastoma cells exposed to a bis(thiosemicarbazonato) metal complex. Biometals 24:117-133.