Antitumor Effects of Two Less-Calcemic Vitamin D Analogs (Paricalcitol and QW-1624F₂-2) in Squamous Cell Carcinoma Cells

Abstract

The active metabolite of vitamin D₃ (1α,25-dihydroxyvitamin D₃, 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 D₂ (paricalcitol) and 1α-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D₃ (QW-1624F₂-2, QW), have anticancer effects in the calcitriol-responsive squamous cell carcinoma (SCC) cell line. Paricalcitol (GI₅₀ = 0.7 nM) and QW (GI₅₀ = 0.001 nM) inhibited SCC cell growth; however, QW was more potent. Paricalcitol (10 nM) and QW (10 nM) induced G₀/G₁ 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^Waf1/Cip1 (p21) and cyclin-dependent kinase 2 (cdk2), and increasing p27^Kip1 (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.

Vitamin D3 analogue EB1089 inhibits the proliferation of human laryngeal squamous carcinoma cells via p57

“…Concerns about the induction of hypercalcemia by calcitriol and the desire for more potent agents have prompted development of less calcemic vitamin D analogues. EB1089 has been shown to regulate the differentiation and proliferation of multiple human cancer cell lines and thus is a potential therapeutic agent for cancers (23,24). In the present study, we have shown for the first time that EB1089 significantly suppresses the growth of human laryngeal SCCs in vitro; this might reflect the general antitumor activity of EB1089.…”

“…Previous studies have shown that the vitamin D analogue, 1-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D 3 , can modulate cell cycle regulators, including increasing mRNA and protein levels of p21 and CDK2 and increasing p27 protein expression in SCCs (24). p57 is a potent inhibitor of several G 1 cyclin/CDK complexes and its overexpression leads to cell cycle arrest in G 1 (25).…”

Synergistic Antileukemic Activity of Carnosic Acid-Rich Rosemary Extract and the 19-nor Gemini Vitamin D Analogue in a Mouse Model of Systemic Acute Myeloid Leukemia

“…Attempts to circumvent this adverse reaction have included the use of high intermittent doses of 1,25D 3 that can be administered to patients with prostate and other cancers without apparent toxicity [4]. Further, a number of vitamin D analogues with lower calcemic effects have been synthesized, which retain the differentiation and antiproliferative activities of the parent compound in myeloid leukemia cells and other cancer cell lines [5,6,7,8]. …”

The conformational dynamics of H2-H3n and S2-H6 in gating ligand entry into the buried binding cavity of vitamin D receptor

“…The use of vitamin D analogues for potential treatment of cancers212223 and autoimmune diseases2425 has been gaining momentum in preclinical research in addition to its classical treatment for osteoporosis. As supraphysiological doses of vitamin D cause hypercalcemia, potential analogues with reduced calcemic effects and improved efficacy are being actively developed.…”