Human MCL1 blocking peptide

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.

RNA-binding protein with serine-rich domain 1 (RNPS1) is essential for modulating mRNA metabolism, but its role in ischemic stroke is unknown. In this study, we found that RNPS1 expression was significantly up-regulated in the brains of ischemic stroke mice and primary cortical neurons after oxygen-glucose deprivation (OGD) treatment. Knockdown of RNPS1 significantly aggravated ischemic brain injury after middle cerebral artery occlusion (MCAO) and promoted neuronal death. In addition, knockdown of RNPS1 exacerbated ischemia induced neuronal apoptosis, and downregulated the expression of anti-apoptotic proteins Bcl-xL and Mcl-1. Our study suggested that RNPS1 might be a potential therapeutic target for alleviating neuronal death in ischemic stroke. (C) 2019 Elsevier Inc. All rights reserved.