FoxM1 inhibitors as potential anticancer drugs.
BACKGROUND
The oncogenic transcription factor forkhead box M1 (FoxM1) is upregulated in a wide range of different carcinomas, while its expression is turned off in terminally differentiated cells. In addition, FoxM1 is involved in tumor invasion, angiogenesis and metastasis. For these reasons, FoxM1 is an appealing target for anticancer therapeutics.


OBJECTIVE
In the quest to develop novel anticancer drugs we decided to target oncogenic transcription factor FoxM1 in tumor cells. Using a cell-based screening system we isolated the thiazole antibiotic siomycin A as inhibitor of FoxM1 transcriptional activity. In addition, we found that because of FoxM1 positive-autoregulation loop siomycin A and another thiazole antibiotic thiostrepton inhibit not only FoxM1 transcriptional activity but also its expression. However, the thiazole antibiotics did not affect the transcriptional activity of other transcription factors studied, suggesting that they may specifically target FoxM1.


CONCLUSIONS
Treatment of human cancer cell lines of different origins with thiazole antibiotics led to apoptosis and downregulation of FoxM1. Our data suggest that thiazole antibiotics that inhibit FoxM1 may be promising drugs against human neoplasia.
Gartel
Andrei L
AL
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors*; D006801:Humans; D010455:Peptides / Q000494:pharmacology*; D013883:Thiostrepton / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D010455:Peptides; C024711:siomycin A; D013883:Thiostrepton