Abstract
The active metabolite of vitamin D<sub>3</sub> (1α,25-dihydroxyvitamin D<sub>3</sub>, calcitriol) has potent antitumor activities in vitro and in vivo in multiple cancers. Concerns about induction of hypercalcemia by calcitriol and the desire for more potent agents have prompted development of less-calcemic vitamin D analogs. These studies demonstrate that two vitamin D analogs, 19-nor-1α,25-dihydroxyvitamin D<sub>2</sub> (paricalcitol) and 1α-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D<sub>3</sub> (QW-1624F<sub>2</sub>-2, QW), have anticancer effects in the calcitriol-responsive squamous cell carcinoma (SCC) cell line. Paricalcitol (GI<sub>50</sub> = 0.7 nM) and QW (GI<sub>50</sub> = 0.001 nM) inhibited SCC cell growth; however, QW was more potent. Paricalcitol (10 nM) and QW (10 nM) induced G₀/G<sub>1</sub> cell cycle arrest and inhibited DNA synthesis by ∼95%. The vitamin D analogs modulated cell cycle regulators, including decreasing mRNA and protein levels of p21<sup>Waf1/Cip1</sup> (p21) and cyclin-dependent kinase 2 (cdk2), and increasing p27<sup>Kip1</sup> (p27) protein expression. Vitamin D analogs induced apoptosis, caspase-3 cleavage and increased expression of pro-apoptotic MEKK-1. Phosphorylation of Akt, MEK and ERK1/2 that promote cell growth and survival were inhibited by vitamin D analogs. The anticancer effects of paricalcitol and QW are comparable to the effect of calcitriol. These less-calcemic vitamin D analogs are as effective as calcitriol in vitro and are promising for prevention and treatment of cancer and other diseases.
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