New potential anti-cancer agents synergize with bortezomib and ABT-737 against prostate cancer.
BACKGROUND
We previously described the identification of a transcriptional inhibitor ARC and FoxM1 inhibitors, thiazole antibiotics, Siomycin A and thiostrepton that were able to induce potent p53-independent apoptosis in cancer cell lines of different origin. Here, we report the characterization of these drugs individually or in combination with ABT-737 and bortezomib on a panel of prostate cancer cell lines.


METHODS
DU 145, LNCaP and PC-3 prostate cancer cells were treated with ARC, Siomycin A and thiostrepton to evaluate their activity as single agents or in combination with ABT-737 and bortezomib to measure their synergistic potential in anti-proliferative and cell cycle assays. Chou-Talalay method was used to quantitate the synergistic interaction. Western blot method was used to determine Mcl-1 and FoxM1 expression and caspase-3 cleavage.


RESULTS
We show that ARC inhibited the viability of prostate cancer cells and induced apoptosis in low nanomolar concentration. It potently downregulated the expression of Mcl-1 and showed synergistic combination effect with Bcl-2 inhibitor ABT-737. Thiazole antibiotics, Siomycin A and thiostrepton inhibited growth, FoxM1 expression and induced cell death in prostate cancer cells in low micromolar concentrations. In addition, thiostrepton and ARC synergistically induced apoptosis in prostate cancer cells following combination treatment with proteasome inhibitor bortezomib. Furthermore, we found that all tested drug combinations were able to induce apoptosis selectively in transformed, but not normal cells of the same origin.


CONCLUSIONS
Based on their in vitro activity as single or combination agents, ARC, Siomycin A and thiostrepton represent potential candidates for drug development against prostate cancer.
Pandit
Bulbul
B
Department of Medicine, University of Illinois, Chicago, Illinois, USA.
Gartel
Andrei L
AL
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology*; D009705:Nucleosides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013883:Thiostrepton / Q000494:pharmacology*
C509961:4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide; C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D001897:Boronic Acids; D009596:Nitrophenols; D009705:Nucleosides; D010455:Peptides; D010879:Piperazines; D011719:Pyrazines; D011743:Pyrimidines; D013449:Sulfonamides; D000069286:Bortezomib; C024711:siomycin A; D013883:Thiostrepton