title: Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells.
abstract: BACKGROUND
  Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects.
  
  
  RESULTS
  In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression.
  
  
  CONCLUSIONS
  Taken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell growth. Disulfiram-sunitinib combination was identified as one of the potent synergistic approaches. Since sunitinib alone has been reported to lack efficacy in prostate cancer clinical trials, our results provide a rationale for novel combinatorial approach to target prostate cancer more efficiently.
authors.affiliation: VTT Technical Research Centre of Finland, and Turku Centre for Biotechnology, University of Turku, Turku, Finland. kirsi.h.ketola@gmail.com
authors.forename: Kirsi
authors.initials: K
authors.lastname: Ketola
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004221:Disulfiram / Q000494:pharmacology / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009361:Neoplasm Invasiveness; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib
chemical_list: C410798:AR protein, human; D015820:Cadherins; D007211:Indoles; D015514:Oncogene Proteins, Fusion; D011758:Pyrroles; D011944:Receptors, Androgen; C515553:TMPRSS2-ERG fusion protein, human; D017430:Prostate-Specific Antigen; D004221:Disulfiram; D000077210:Sunitinib