CHIR-124, a novel potent inhibitor of Chk1, potentiates the cytotoxicity of topoisomerase I poisons in vitro and in vivo Journal Article
| Authors: | Tse, A. N.; Rendahl, K. G.; Sheikh, T.; Cheema, H.; Aardalen, K.; Embry, M.; Ma, S.; Moler, E. J.; Zhi, J. N.; De Menezes, D. E. L.; Hibner, B.; Gesner, T. G.; Schwartz, G. K. |
| Article Title: | CHIR-124, a novel potent inhibitor of Chk1, potentiates the cytotoxicity of topoisomerase I poisons in vitro and in vivo |
| Abstract: | Purpose: Chk1 kinase is a critical regulator of both S and G2-M phase cell cycle checkpoints in response to DNA damage. This study aimed to evaluate the biochemical, cellular, and antitumor effects of a novel Chk1 inhibitor, CHIR124. Experimental Design: CHIR-124 was evaluated for its ability to abrogate cell cycle checkpoints, to potentiate cytotoxicity, and to inhibit Chk1-mediated signaling induced by topoisomerase I poisons in human tumor cell line and xenograft models. Results: CHIR-124 is a quinolone-based small molecule that is structurally unrelated to other known inhibitors of Chk1. It potently and selectively inhibits Chk1 in vitro (IC50 = 0.0003 μmol/L). CHIR-124 interacts synergistically with topoisomerase poisons (e.g., camptothecin or SN-38) in causing growth inhibition in several p53-mutant solid tumor cell lines as determined by isobologram or response surface analysis. CHIR-124 abrogates the SN-38- induced S and G2-M checkpoints and potentiates apoptosis in MDA-MD-435 breast cancer cells. The abrogation of the G2-M checkpoint and induction of apoptosis by CHIR-124 are enhanced by the loss of p53. We have also shown that CHIR-124 treatment can restore the level of cdc25A protein, which is normally targeted by Chk1 for degradation following DNA damage, indicating that Chk1 signaling is suppressed in the presence of CHIR-124. Finally, in an orthotopic breast cancer xenograft model, CHIR-124 potentiates the growth inhibitory effects of irinotecan by abrogating the G2-M checkpoint and increasing tumor apoptosis. Conclusions: CHIR-124 is a novel and potent Chk1 inhibitor with promising antitumor activities when used in combination with topoisomerase I poisons. © 2007 American Association for Cancer Research. |
| Keywords: | controlled study; unclassified drug; human cell; cisplatin; doxorubicin; drug potentiation; monotherapy; nonhuman; antineoplastic agents; antineoplastic agent; mitosis; mouse; animals; mice; dna damage; cell cycle s phase; drug inhibition; apoptosis; breast cancer; protein kinases; protein degradation; antineoplastic combined chemotherapy protocols; animal experiment; animal model; 7 ethyl 10 hydroxycamptothecin; camptothecin; combination chemotherapy; antineoplastic activity; cytotoxicity; drug potency; drug structure; tumor xenograft; mice, scid; cell line, tumor; protein p53; irinotecan; drug synergism; cancer inhibition; drug mechanism; enzyme inhibitors; cell cycle g2 phase; cell cycle m phase; protein tyrosine phosphatase; neoplasm transplantation; inhibitory concentration 50; checkpoint kinase 1; models, chemical; dna topoisomerase; dna topoisomerases, type i; random allocation; protein serine threonine kinase inhibitor; quinolines; quinuclidines; 7 hydroxystaurosporine; chir 124; response surface method |
| Journal Title: | Clinical Cancer Research |
| Volume: | 13 |
| Issue: | 2 I |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2007-01-15 |
| Start Page: | 591 |
| End Page: | 602 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-06-1424 |
| PUBMED: | 17255282 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 40" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus" |
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