Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, 41500 Biopolis, Larissa, Greece.
Division of Endocrinology, Interbalkan Medical Center, 55535 Thessaloniki, Greece.
Arch Biochem Biophys. 2021 Jun 15;704:108889. doi: 10.1016/j.abb.2021.108889. Epub 2021 Apr 22.
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%O) or hypoxia (1%O). 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.
大量的流行病学、临床前和体外实验数据强烈表明，维生素 D 的生物活性形式——骨化三醇具有抗癌潜力。然而，为了实施基于维生素 D 的癌症治疗，应该抑制在癌细胞中由过表达的 CYP24A1 羟化酶引起的骨化三醇的失活增加。目前，抑制这种酶的表达或活性被认为是抗癌治疗策略的重要方面。在此，我们研究了染料木黄酮、大豆苷元、芒柄花素和山柰酚对骨化三醇在常氧（21%O）或缺氧（1%O）条件下诱导的肝癌细胞 Huh7 中 CYP24A1 基因表达的影响。我们证明骨化三醇在常氧和缺氧条件下诱导 CYP24A1，但在缺氧条件下诱导作用更强，缺氧是实体瘤的典型微环境。在异黄酮染料木黄酮、大豆苷元和芒柄花素存在的情况下，这种诱导作用在常氧条件下被阻断到对照水平，而在缺氧条件下，这些化合物之间的抑制效果存在一些差异，其中染料木黄酮≥大豆苷元>芒柄花素。同时，山柰酚在抑制 CYP24A1 基因表达方面完全无效。
