Novel piperidine derivatives as colchicine binding site inhibitors induce apoptosis and inhibit epithelial-mesenchymal transition against prostate cancer PC3 cells

Abstract

Tubulin polymerisation inhibitors that target colchicine binding site were powerful anticancer agents. Although along the years many colchicine binding site inhibitors (CBSIs) have been reported, few piperidine derivatives were identified as CBSIs. In this regard, we focussed efforts on the piperidine as a promising chemotype to develop potent CBSIs. Herein, novel piperidine derivatives were synthesised and evaluated for their antiproliferative activities. Among them, compound 17a displayed powerful anticancer activity with the IC 50 value of 0.81 mM against PC3 cells, which was significantly better than 5-fluorouracil. It could inhibit tubulin polymerisation binding at the colchicine site and inhibit the tumour growth in vitro and in vivo. Further biological studies depicted that 17a suppressed the colony formation, induced apoptosis, and inhibited epithelial-mesenchymal transition against PC3 cells. These results revealed that compound 17a is a promising colchicine binding site inhibitor for the treatment of cancer and it is worthy of further exploitation.

Anticancer Applications and Pharmacological Properties of Piperidine and Piperine: A Comprehensive Review on Molecular Mechanisms and Therapeutic Perspectives

“…Several piperidine derivatives were synthesized among them one such derivative is compound 17a, which shows good anti-prostate cancer activity. Fu et al (2020) studied the effect of compound 17a on PC3 (prostate cancer cell line) and found that it inhibits PC3 proliferation in a concentrationdependent manner. Compound 17a also resulted in inducing apoptosis in PC3 cells by decreasing the expression level of XIAP and BCL-2 and increasing the level of BAX accordingly in a concentration-dependent manner (Samykutty et al, 2013).…”

Inhibition of CYP1A1 Alleviates Colchicine-Induced Hepatotoxicity

“…Colchicine is a microtubule inhibitor that can bind to tubulin dimers to prevent tubulin conversion and was found to prevent cell division during mitosis in vitro [ 21 ], which is one of the major factors causing liver toxicity. Previous studies on hepatotoxicity demonstrated that colchicine regulated the ubiquitin–proteasome pathway 3 to induce Mallory bodies [ 22 ].…”

Research Trend and Detailed Insights into the Molecular Mechanisms of Food Bioactive Compounds against Cancer: A Comprehensive Review with Special Emphasis on Probiotics

“…It restricted the cell cycle in the G0/G1 phase [ 44 ]. Piperidine also inhibited prostate cancer cell growth by the induction of apoptosis [ 45 ]. It increased the levels of pro-apoptotic Bax and decreased the expression of BcL-2 and XIAP [ 24 ].…”