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Targeting CDK 9 for treatment of colorectal cancer

Rahaman, Muhammed H., Lam, Frankie, Zhong, Longjin, Teo, Theodosia, Adams, Julian, Yu, Mingfeng, Milne, Robert W., Pepper, Chris, Lokman, Noor A., Ricciardelli, Carmela, Oehler, Martin and Wang, Shudong 2019. Targeting CDK 9 for treatment of colorectal cancer. Molecular Oncology 13 (10) , pp. 2178-2193. 10.1002/1878-0261.12559

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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‐tumor 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 downregulated multiple pro‐survival factors at the mRNA level. Its in vivo anti‐tumor efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumors. CDKI‐73 significantly inhibited tumor growth (***p < 0.001) without overt toxicity. Analysis of the tumor tissues collected from the xenografted animals confirmed that the in vivo anti‐tumor 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Wiley
ISSN: 1574-7891
Date of First Compliant Deposit: 19 August 2019
Date of Acceptance: 7 August 2019
Last Modified: 10 Oct 2019 13:34
URI: http://orca.cf.ac.uk/id/eprint/124991

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