Targeting CDK9 for treatment of colorectal cancer
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 o...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-10-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.12559 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Muhammed H. Rahaman |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cbaa876250d345bd9ed140b6e56eb1f2 |
| institution | OA Journals |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2019-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-cbaa876250d345bd9ed140b6e56eb1f22025-08-20T01:47:37ZengWileyMolecular Oncology1574-78911878-02612019-10-0113102178219310.1002/1878-0261.12559Targeting CDK9 for treatment of colorectal cancerMuhammed H. Rahaman0Frankie Lam1Longjin Zhong2Theodosia Teo3Julian Adams4Mingfeng Yu5Robert W. Milne6Chris Pepper7Noor A. Lokman8Carmela Ricciardelli9Martin K. Oehler10Shudong Wang11Centre for Drug Discovery and Development School of Pharmacy and Medical Sciences University of South Australia Cancer Research Institute Adelaide SA AustraliaCentre for Drug Discovery and Development School of Pharmacy and Medical Sciences University of South Australia Cancer Research Institute Adelaide SA AustraliaCentre for Drug Discovery and Development School of Pharmacy and Medical Sciences University of South Australia Cancer Research Institute Adelaide SA AustraliaCentre for Drug Discovery and Development School of Pharmacy and Medical Sciences University of South Australia Cancer Research Institute Adelaide SA AustraliaCentre for Drug Discovery and Development School of Pharmacy and Medical Sciences University of South Australia Cancer Research Institute Adelaide SA AustraliaCentre for Drug Discovery and Development School of Pharmacy and Medical Sciences University of South Australia Cancer Research Institute Adelaide SA AustraliaCentre for Drug Discovery and Development School of Pharmacy and Medical Sciences University of South Australia Cancer Research Institute Adelaide SA AustraliaSchool of Medicine Cardiff University, Health Park UKDiscipline of Obstetrics and Gynaecology Adelaide Medical SchoolUniversity of Adelaide SA AustraliaDiscipline of Obstetrics and Gynaecology Adelaide Medical SchoolUniversity of Adelaide SA AustraliaDiscipline of Obstetrics and Gynaecology Adelaide Medical SchoolUniversity of Adelaide SA AustraliaCentre for Drug Discovery and Development School of Pharmacy and Medical Sciences University of South Australia Cancer Research Institute Adelaide SA AustraliaColorectal 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.https://doi.org/10.1002/1878-0261.12559anti‐proliferationapoptosiscancer therapyCDK9colorectal cancerRNAPII transcription |
| spellingShingle | 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 Targeting CDK9 for treatment of colorectal cancer Molecular Oncology anti‐proliferation apoptosis cancer therapy CDK9 colorectal cancer RNAPII transcription |
| title | Targeting CDK9 for treatment of colorectal cancer |
| title_full | Targeting CDK9 for treatment of colorectal cancer |
| title_fullStr | Targeting CDK9 for treatment of colorectal cancer |
| title_full_unstemmed | Targeting CDK9 for treatment of colorectal cancer |
| title_short | Targeting CDK9 for treatment of colorectal cancer |
| title_sort | targeting cdk9 for treatment of colorectal cancer |
| topic | anti‐proliferation apoptosis cancer therapy CDK9 colorectal cancer RNAPII transcription |
| url | https://doi.org/10.1002/1878-0261.12559 |
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