Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells

Abstract

Signaling of cell differentiation is one of the important physiological functions of the activated vitamin D receptor (VDR). Activation of the VDR can be achieved not only by 1α,25-dihydroxyvitamin D 3 (1,25D), the natural ligand, but also by a large number of its analogs. These include a category containing two side chains emanating at C-20, generally referred to as Gemini. The introduction of a cyclopropyl moiety as part of the pro-R side chain provides modified Gemini compounds with increased steric requirement and decreased chain flexibility; the biological consequences of this novel structural variant are subject of this investigation. In general, the resulting 1α,25-dihydroxy-(4-hydroxy-4-methyl-pentyl)-21,22-cis-cyclo-cholecalciferols reduced had differentiation and transcriptional potency and induced cell cycle arrest less effciently, as shown by a decrease in G1/S ratio, when compared to 1,25D. Modifying their calcitriol side chain in the form of a 4-hydroxy-4-trifluoromethyl-5,5,5-trifluoropent-2-ynyl moiety, however, resulted in pronounced induction of differentiation in 1,25D-sensitive and moderate level of differentiation in 1,25D-resistant leukemia cells.

Vitamin D, Its Role in Recovery after Muscular Damage Following Exercise

“…Part of this interest is due to the finding that vitamin D receptor (VDR) is present in muscular cells. In this tissue, vitamin D regulates cell proliferation and differentiation of muscle cells as well as the transport of calcium and phosphate to intracellular compartments [ 4 ]. In this context, Ahmed et al used vitamin D supplementation to reverse myositis-myalgia in patients treated with statins and presenting vitamin D deficiency [ 5 ].…”

Muscular effects of vitamin D in young athletes and non-athletes and in the elderly

“…3 In muscles, vitamin D affects cell proliferation and differentiation and the transport of calcium and phosphate across muscle cell membranes, while it modulates phospholipid metabolism. 4 Vitamin D additionally suppresses the expression of myostatin, a negative regulator of muscle mass, while it up-regulates the expression of follistatin and insulin-like growth factor 2.…”

Relationship between 25(OH)D levels and athletic performance in elite Polish judoists

“…The genomic effects rely on heterodimerisation of the calcitriol complex with retinoic x receptor (RXR) acting on vitamin D response elements (VDREs). Vitamin D affects cell proliferation and differentiation, and the transport of calcium and phosphate across muscle cell membranes, while modulating phospholipid metabolism [ 2 ]. Calcitriol signalling alters the expression of myotubular sizes, indicating a direct positive effect on the contractile filaments and thus muscle strength, while it prevents muscular degeneration and reverses myalgia.…”