title: Vitamin D Signaling Modulators in Cancer Therapy.
abstract: The antiproliferative and pro-apoptotic effects of 1α,25-dihydroxycholecalciferol (1,25(OH)2D3, 1,25D3, calcitriol) have been demonstrated in various tumor model systems in vitro and in vivo. However, limited antitumor effects of 1,25D3 have been observed in clinical trials. This may be attributed to a variety of factors including overexpression of the primary 1,25D3 degrading enzyme, CYP24A1, in tumors, which would lead to rapid local inactivation of 1,25D3. An alternative strategy for improving the antitumor activity of 1,25D3 involves the combination with a selective CYP24A1 inhibitor. The validity of this approach is supported by numerous preclinical investigations, which demonstrate that CYP24A1 inhibitors suppress 1,25D3 catabolism in tumor cells and increase the effects of 1,25D3 on gene expression and cell growth. Studies are now required to determine whether selective CYP24A1 inhibitors+1,25D3 can be used safely and effectively in patients. CYP24A1 inhibitors plus 1,25D3 can cause dose-limiting toxicity of vitamin D (hypercalcemia) in some patients. Dexamethasone significantly reduces 1,25D3-mediated hypercalcemia and enhances the antitumor activity of 1,25D3, increases VDR-ligand binding, and increases VDR protein expression. Efforts to dissect the mechanisms responsible for CYP24A1 overexpression and combinational effect of 1,25D3/dexamethasone in tumors are underway. Understanding the cross talk between vitamin D receptor (VDR) and glucocorticoid receptor (GR) signaling axes is of crucial importance to the design of new therapies that include 1,25D3 and dexamethasone. Insights gained from these studies are expected to yield novel strategies to improve the efficacy of 1,25D3 treatment.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Candace S
authors.initials: CS
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA; Inova Dwight and Martha Schar Cancer Institute, Falls Church, Virginia, USA. Electronic address: Donald.Trump@inova.org.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Trump
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014807:Vitamin D / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; D014807:Vitamin D
keywords: 1,25D(3); CYP24A1; CYP24A1 inhibitor; Cancer; GR; Glucocorticoids; Hypercalcemia; VDR; Vitamin D; Vitamin D analogs