Targeting CDK9 for treatment of colorectal cancer.pdf (5.12 MB)
Targeting CDK9 for treatment of colorectal cancer
journal contribution
posted on 2023-06-10, 04:55 authored by Muhammed H Rahaman, Frankie Lam, Longjin Zhong, Theodosia Teo, Julian Adams, Mingfeng Yu, Robert W Milne, Christopher PepperChristopher Pepper, Noor A Lokman, Carmela Ricciardelli, Martin K Oehler, Shudong WangColorectal 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.
History
Publication status
- Published
File Version
- Published version
Journal
Molecular OncologyISSN
1574-7891Publisher
WileyExternal DOI
Issue
10Volume
13Page range
2178-2193Event location
United StatesDepartment affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-09-29First Open Access (FOA) Date
2022-09-29First Compliant Deposit (FCD) Date
2022-09-29Usage metrics
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