Targeting CDK9 for treatment of colorectal cancer.

Abstract

Colorectal cancer (CRC) remains one of the most lethal human malignancies, and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin-dependent kinase 9 (CDK9), which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI-73, one of the most potent and pharmacologically superior CDK9 inhibitors, has demonstrated excellent anti-tumour efficacy against several types of cancers. In this study, we evaluated its therapeutic potential against CRC. CDKI-73 elicited high cytotoxicity against all colon cancer cell lines tested. Cell cycle and apoptosis analysis in HCT 116 and HT29 cells revealed that CDKI-73 induced cell death without accumulation of DNA at any phase of the cell cycle. Moreover, it caused depolarisation of mitochondrial membrane, leading to caspase-independent apoptosis. Knockdown by shRNA demonstrated the CDK9-targeted mechanism of CDKI-73, which also affected the Mnk/eIF4E signalling axis. In addition, RT-qPCR analysis showed that CDKI-73 down-regulated multiple pro-survival factors at the mRNA level. Its in vivo anti-tumour efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumours. CDKI-73 significantly inhibited tumour growth (***P < 0.001) without overt toxicity. Analysis of the tumour tissues collected from the xenografted animals confirmed that the in vivo anti-tumour efficacy was associated with CDK9 targeting of CDKI-73. Overall, this study provides compelling evidence that CDKI-73 is a promising drug candidate for treating colorectal cancer.

• Authors: Muhammed H Rahaman, Frankie Lam, Longjin Zhong, Theodosia Teo, Julian Adams, Mingfeng Yu, Robert W Milne, Chris Pepper, Noor A Lokman, Carmela Ricciardelli, Martin K Oehler, Shudong Wang
• Journal: Molecular oncology (Mol Oncol) Vol. 13 Issue 10 Pg. 2178-2193 (10 2019) ISSN: 1878-0261 [Electronic] United States
• PMID: 31398271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• 3-(5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)benzenesulfonamide
• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyrimidines
• Sulfonamides
• CDK9 protein, human
• Cyclin-Dependent Kinase 9

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, metabolism)
• Cyclin-Dependent Kinase 9 (antagonists & inhibitors, metabolism)
• Female
• HCT116 Cells
• HT29 Cells
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Sulfonamides (pharmacology, therapeutic use)