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- Title
Dual targeting of MDM2 with a novel small-molecule inhibitor overcomes TRAIL resistance in cancer.
- Authors
Singh, Anup Kumar; Chauhan, Shikha S.; Singh, Sudhir Kumar; Verma, Ved Vrat; Singh, Akhilesh; Arya, Rakesh Kumar; Maheshwari, Shrankhla; Akhtar, Md. Sohail; Sarkar, Jayanta; Rangnekar, Vivek M.; Chauhan, Prem M. S.; Datta, Dipak
- Abstract
Mouse double minute 2 (MDM2) protein functionally inactivates the tumor suppressor p53 in human cancer. Conventional MDM2 inhibitors provide limited clinical application as they interfere only with the MDM2-p53 interaction to release p53 from MDM2 sequestration but do not prevent activated p53 from transcriptionally inducing MDM2 expression. Here, we report a rationally synthesized chalcone-based pyrido[b]indole, CPI-7c, as a unique small-molecule inhibitor of MDM2, which not only inhibited MDM2-p53 interaction but also promoted MDM2 degradation. CPI-7c bound to both RING and N-terminal domains of MDM2 to promote its ubiquitin-mediated degradation and p53 stabilization. CPI-7c-induced p53 directly recruited to the promoters of DR4 and DR5 genes and enhanced their expression, resulting in sensitization of TNFrelated apoptosis-inducing ligand (TRAIL)-resistant cancer cells toward TRAIL-induced apoptosis. Collectively, we identified CPI-7c as a novel small-molecule inhibitor of MDM2 with a unique two-prong mechanism of action that sensitized TRAILresistant cancer cells to apoptosis by modulating the MDM2-p53-DR4/DR5 pathway.
- Subjects
TUMOR suppressor proteins; CHALCONE synthase; SMALL molecules; APOPTOSIS inhibition; CANCER cell growth; PYRIDONE derivatives
- Publication
Carcinogenesis, 2016, Vol 37, Issue 11, p1027
- ISSN
0143-3334
- Publication type
Article
- DOI
10.1093/carcin/bgw088