Chemical Biology Drug Sensitivity Screen Identifies Sunitinib as Synergistic Agent with Disulfiram in Prostate Cancer Cells

Abstract

BackgroundCurrent 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.Methods and FindingsIn 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.ConclusionsTaken 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.

Schlafen 12 expression modulates prostate cancer cell differentiation

“…Loss of E-cadherin in prostate cancer correlates with increased Gleason score and reduced survival (40). In contrast, treatment of prostate cancer cells with vitamin D analogs (41) or a disulfiram-sunitinib combination (42) increase E-cadherin and other differentiation markers and reduce proliferation. Slfn3 overexpression in human HCT-116 colon cancer cells similarly drives differentiation and increases E-cadherin levels (43).…”

A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

“…Disulfiram has previously been documented to potentiate the effect of several chemotherapy agents in vitro: cisplatin [128], gemcitabine [101, 129] temozolomide [130], paclitaxel [100], docetaxel [131], cyclophosphamide [132], 5-fluorouracil [101, 102], doxorubicin [99], sunitinib [104], and BCNU [133]. Currently, disulfiram is in Phase I clinical trials in metastatic melanoma, in hormone refractory cancers with lung and liver metastases (, identifiers NCT00256230 and NCT00742911) as well as in prostate cancer (identifier: NCT01118741).…”

Preparation and characterisation of Kolliphor® P 188 and P 237 solid dispersion oral tablets containing the poorly water soluble drug disulfiram

“…Disulfiram (DSF), which has been safely used as an anti-alcoholism drug for over 60 years, has been shown to have high cytotoxicity to a wide range of cancers while sparing their normal counterparts (Brar et al, 2004;Cen et al, 2002Cen et al, , 2004Chen et al, 2006;Lljin et al, 2009;Ketola et al, 2012;Liu et al, 2012;Yip et al, 2011). DSF has also been shown to potentiate the cytotoxic effect of anticancer drugs while protecting normal cells (Dufour et al, 1993;Verma et al, 1990).…”