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

Vitamin D and Hypoxia: Points of Interplay in Cancer

“…Given that calcitriol can directly affect HIF-1/2α mRNA expression, translation, and modifications, it is highly plausible that many of its anticancer abilities are a result of calcitriol interfering with HIF-associated signaling. As hypoxia can also directly affect calcitriol hydroxylation (due to lack of oxygen) or increase the expression of its inactivating enzymes (CYP24A1; [ 20 ]), calcitriol or newly developed analogs can defend against cancer development. However, finding the optimal clinical application of the vitamin D system is a challenging and multifaceted task that demands widespread investigation, taking into consideration the hypoxic nature of many human cancers.…”

“…Although these data indicate the great prospect of calcitriol as an anticancer agent, there are mainly two limiting factors that hinder its broader use: (i) its side effects when calcitriol is administered in high doses (oral calcitriol dose ranging from 0.5–2.5 μg/kg daily with a maximum tolerated dose being 1.5 μg or 2.5 μg depending on the study) [ 208 ], and (ii) the decreased availability of calcitriol due to its enzymatic deactivation by the calcitriol-induced CYP24A1 gene [ 32 ]. Concerning the latter, hypoxia induces CYP24A1 levels [ 20 , 209 ] and, at the same time, it was found that in breast cancers, CYP27B1 levels drop while CYP24A1 levels rise [ 210 ]. Moreover, tissue hypoxia (though not in cancer tissues) caused a drop in VDR, vitamin D binding protein (VDBP), and 25-hydroxylase (CYP2R1) levels while it increased CYP27B1 and CYP24A1 levels [ 211 ].…”

“…Hypercalcemia, the major side effect of vitamin D, has strongly hindered the calcitriol clinical applications [ 18 , 19 ]. Moreover, accumulating data suggest that cancer cells employ several mechanisms that either reduce cellular calcitriol levels by overexpression of calcitriol deactivating enzyme CYP24A1, remarkably induced by hypoxia, to catalyze its inactivation [ 20 ] or diminish its function to protect themselves from the antitumorigenic effects of vitamin D [ 16 , 17 ]. Such maladaptive mechanisms are often dysregulated in solid tumors due to the development of a microenvironment characterized by reduced oxygen availability (hypoxia) caused by irregular vascularization and increased cell proliferation rates.…”