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.
Highlights
Colorectal cancer (CRC) is one of the most lethal malignant neoplasms worldwide
The current study explored the therapeutic potential of CDKI-73, an oral and highly potent Cyclin-dependent kinase 9 (CDK9) inhibitor, by examining its effect on human colon cancer cell lines (HCCL) of different clinical relevance
CDKI-73 was identified through structure-guided medicinal chemistry and is one of the most potent among existing CDK9 inhibitors (Shao et al, 2013; Walsby et al, 2014)
Summary
Colorectal cancer (CRC) is one of the most lethal malignant neoplasms worldwide. It shows substantial genetic heterogeneity and aberration in multiple cellular pathways among the subtypes (Hahn et al, 2016). Morphological and molecular features of CRC assisted to create a defined classification of the Abbreviations 4E-BP, eIF4E-binding protein; CDK, cyclin-dependent kinase; CRC, colorectal cancer; eIF4E, eukaryotic translation initiation factor 4E; Erk, extracellular signal-regulated kinase; HCCLs, human colon cancer cell lines; IC50, half-maximal inhibitory concentration; IHC, immunohistochemisty; IP, intraperitoneal injection; JC-1, 5,50,6,60-tetrachloro-1,103,30-tetraethylbenzimidazolylcarbocyanine iodide; KD, knockdown; MAPK, mitogen-activated protein kinase; MMP, mitochondrial membrane potential; Mnk, mitogen-activated protein kinaseinteracting kinase; mTOR, mammalian target of rapamycin; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PARP, poly (ADP-ribose) polymerase; PI, propidium iodide; PO, oral dosing; p-RNAPIISer, phosphorylated RNAPII serine 2; Q3D, once every 3 days dosing; Q7D, once-a-week dosing; RNAPII, RNA polymerase II; rpS6, ribosomal protein S6; RT-qPCR, real-time quantitative polymerase chain reaction; shRNA, short hairpin RNA; XIAP, X-linked inhibitor of apoptosis.
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