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© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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 (***< 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.

Details

Title
Targeting CDK9 for treatment of colorectal cancer
Author
Rahaman, Muhammed H 1 ; Lam, Frankie 1 ; Zhong, Longjin 1 ; Teo, Theodosia 1 ; Adams, Julian 1 ; Yu, Mingfeng 1 ; Milne, Robert W 1 ; Pepper, Chris 2 ; Lokman, Noor A 3 ; Ricciardelli, Carmela 3 ; Oehler, Martin K 3 ; Wang, Shudong 1 

 Centre for Drug Discovery and Development, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, Adelaide, SA, Australia 
 School of Medicine, Cardiff University, Health Park, UK 
 Discipline of Obstetrics and Gynaecology, Adelaide Medical School, University of Adelaide, SA, Australia 
Pages
2178-2193
Section
Research Articles
Publication year
2019
Publication date
Oct 2019
Publisher
John Wiley & Sons, Inc.
ISSN
15747891
e-ISSN
18780261
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2297847697
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.