Inhibition of calcitriol inactivating enzyme CYP24A1 gene expression by flavonoids in hepatocellular carcinoma cells under normoxia and hypoxia

Abstract

A vast number of epidemiological, preclinical and in vitro experimental data strongly indicate the anticancer potential of calcitriol, the biologically active form of vitamin D. However, for the implementation of a vitamin D based cancer therapy the increased deactivation of calcitriol in cancer cells by overexpressed CYP24A1 hydroxylase should be suppressed. Inhibition of this enzyme expression or activity nowadays is considered as important aspect of anticancer therapeutic strategies. Herein, we investigated the impact of genistein, biochanin A, formonentin and kaempferol on the expression of the CYP24A1 gene induced by calcitriol in hepatocellular cancer cells Huh7 under normoxia (21%O2) or hypoxia (1%O2). We demonstrate that calcitriol induces CYP24A1 under normoxia and hypoxia, but this induction is significantly more potent under hypoxia, the typical microenvironment of solid tumors. In the presence of isoflavones genistein, biochanin A and formononetin, this induction is abrogated to the control levels under normoxia, while under hypoxia there is some differentiation in suppression efficacy between these compounds with genistein ≥ biochanin > formononetin. At the same time, kaempferol turned out to be completely ineffective in the suppression of CYP24A1 gene expression. © 2021 Elsevier Inc.