New Antibiotics May Target Cancer-Causing Proteins
8/12/2009
WEDNESDAY, Aug. 12 (HealthDay News) -- Scientists are closer to understanding how a recently approved class of antibiotics may work against cancer.
The drugs, called
thiazole antibiotics, appear to block a cellular protein called FoxM1, one of the most over-produced proteins in cancer cells, according to researchers at the University of Illinois at Chicago College of Medicine. FoxM1 is believed to play an important role in causing cells to become cancerous and may present a promising target for future anti-cancer treatments.
The researchers also found that
thiazoles may inhibit proteasomes, a molecular complex within cells that disposes of old proteins marked for destruction. Recently, a number of proteasome inhibitors have shown promise against cancer. One of these inhibitors, bortezomib (Velcade), has proven effective against a number of cancers, including myeloma and certain forms of lymphoma.
The new research, which appears in the online journal
PLoS ONE, points to the possible anti-cancer use of thiazoles in the future. In a university news release, study author Andrei Gartel, an associate professor of molecular genetics, said that
by using thiazole antibiotics in combination with well-known proteasome inhibitors, "we may see a synergy that allows us to markedly reduce the dose of any one of these drugs and still effectively kill the cancer cells."
Prostate. 2010 Jan 7. [Epub ahead of print]
New potential anti-cancer agents synergize with bortezomib and ABT-737 against prostate cancer.
Pandit B,
Gartel AL.
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
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. Prostate (c) 2010 Wiley-Liss, Inc.
PMID: 20058240 [PubMed - as supplied by publisher]
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