The antitumor efficacy of calcitriol: preclinical studies.
Studies in our laboratory demonstrate that vitamin D (1,25 dihydroxycholecalciferol or calcitriol) has significant antitumor activity in vitro and in vivo in murine and human squamous cell, prostate, lung, pancreatic and myeloma model systems. Calcitriol induces G0/G1 arrest, modulates p27 and p21, the cyclin-dependent kinase (cdk) inhibitors implicated in G1 arrest, and induces cleavage of caspase 3, PARP and the mitogen-activated protein kinase (MEK) in a caspase-dependent manner. Calcitriol also decreases phospho-Erk (P-Erk) and phospho-Akt (P-Akt), kinases that regulate cell survival pathways and up-regulate the pro-apoptotic signaling molecule, MEKK-1. Glucocorticoids enhance calcitriol-mediated activities pre-clinically in vitro and in vivo. Dexamethasone (dex) significantly potentiated the antitumor effect of calcitriol and decreased calcitriol-induced hypercalcemia. Both in vitro and in vivo, dex increased vitamin D receptor (VDR) ligand binding in the tumor while decreasing binding in intestinal mucosa, the site of calcium absorption. These studies demonstrated that calcitriol has significant antiproliferative activity in a number of pre-clinical model systems and form the groundwork for on-going clinical studies investigating calcitriol as an anticancer agent.
Johnson
Candace S
CS
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. candace.johnson@roswellpark.org
Muindi
Josephia R
JR
Hershberger
Pamela A
PA
Trump
Donald L
DL
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology
D005938:Glucocorticoids; D003907:Dexamethasone; D002117:Calcitriol