Abstract. Methyl jasmonate potentially induces the differentiation of human myeloid leukemia cells and inhibits their proliferation; it may induce the differentiation and apoptosis of human lymphocytic leukemia cells, but does not exert a damaging effect on normal lymphocytes. In the present study, the anticancer effect of methyl jasmonate on human colorectal cancer cells was investigated. Cell viability and apoptosis was assessed using a Cell Counting kit-8 assay and flow cytometry, respectively. Methyl jasmonate suppressed cell viability and induced apoptosis in human colorectal cancer cells. Additionally, methyl jasmonate increased the activation of caspase-3, inhibited the expression levels of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and the Wnt/β-catenin pathway in human colorectal cancer. Downregulation of EZH2 expression enhanced the anticancer effect of methyl jasmonate on human colorectal cancer cells through suppression of the Wnt/β-catenin pathway. Thus, EZH2 downregulation promotes the anticancer effect of methyl jasmonate by inducing apoptosis in human colorectal cancer cells through the Wnt/β-catenin pathway.
Context: Hydroxycamptothecin (HCPT) has antitumor activity in various cancers, but its poor bioavailability and efflux limit its clinical application. Verapamil has been demonstrated to improve the bioavailability of many drugs. However, the effect of verapamil on the pharmacokinetics of HCPT was not clear. Objective: The effect of verapamil on the pharmacokinetics of HCPT was investigated to clarify the drug-drug interaction between HCPT and verapamil. Materials and methods: The pharmacokinetic profiles of oral administration of HCPT (50 mg/kg) in two group of Sprague-Dawley rats (six rats each), with pre-treatment of verapamil (10 mg/kg/day) for 7 days were investigated, with the group without verapamil pre-treatment as control. Additionally, the metabolic stability and transport of HCPT in the presence or absence of verapamil were also investigated with the employment of the rat liver microsomes and Caco-2 cell transwell model. Results: Verapamil significantly increased the peak plasma concentration (from 91.97 ± 11.30 to 125.30 ± 13.50 ng/mL), and decrease the oral clearance (from 63.85 ± 10.79 to 32.95 ± 6.17 L/h/kg). The intrinsic clearance rate was also significantly decreased (from 39.49 ± 0.42 to 28.64 ± 0.30 lL/min/mg protein) by the preincubation of verapamil. The results of Caco-2 cell transwell experiments showed the efflux of HCPT was inhibited by verapamil, as the efflux ratio decreased from 1.82 to 1.21. Discussion and conclusions: The system exposure of HCPT was increased by verapamil. Verapamil may exert this effect through inhibiting the activity of CYP3A4 or P-gp, which are related to the metabolism and transport of HCPT.
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