Antiproliferative activity of side-chain truncated vitamin D analogs (PRI-1203 and PRI-1204) against human malignant melanoma cell lines

• Published in: European journal of pharmacology Vol. 881; p. 173170
• Main Authors: Piotrowska, Anna, Wierzbicka, Justyna, Kwiatkowska, Kamila, Chodyński, Michał, Kutner, Andrzej, Żmijewski, Michał A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.08.2020
• Subjects: Active Transport, Cell Nucleus; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Calcitriol - analogs & derivatives; Calcitriol - chemistry; Calcitriol - pharmacology; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Enzyme Induction; Gene Expression Regulation, Neoplastic; Humans; Isomerism; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Neoplasm Invasiveness; Pregnacalciferol; PRI-1203; PRI-1204; Receptors, Calcitriol - agonists; Receptors, Calcitriol - metabolism; Side-chain truncated vitamin D analogs; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Structure-Activity Relationship; Vitamin D; Vitamin D3 24-Hydroxylase - biosynthesis; Vitamin D3 24-Hydroxylase - genetics; Side-chain truncated vitamin D analogs; Vitamin D; PRI-1204; Pregnacalciferol; PRI-1203; Melanoma
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173170

Vitamin D compounds are versatile molecules widely considered as promising agents in cancer prevention and treatment, including melanoma. Previously we investigated series of double point modified vitamin D2 analogs as well as non-calcemic 20S-hydroxyvitamin D3 and 21-hydroxypregnacalciferol as to their anti-melanoma activity. Surprisingly, short side-chain vitamin D analogs were found to be biologically active compounds. Thus, here we tested novel derivatives of pregnacalciferol with an additional hydroxyl at the end of the truncated side chain, PRI-1203 and PRI-1204, as to their potency against human melanoma A375 and RPMI7951 cell lines. Tested compounds are geometric isomers, with 19-methylene positioned in PRI-1203 like in a calcitriol molecule, but reversed in the PRI-1204 analog to the (5E,7E) geometry (5,6-trans). We noticed a decrease in cells viability exerted by PRI-1203. The antiproliferative effect of PRI-1204 was very low, emphasizing the importance of the natural 19-methylene geometry in the PRI-1203. PRI-1203 was also effective in inhibition of A375 melanoma cells migration. PRI-1203, but not PRI-1204, increased the percentage of A375 and RPMI7951 melanoma cells in the G0/G1 phase of cell cycle, possibly in a p21 and p27 independent manner. Both, analogs have very low effect on the level of CYP24A1 mRNA, in comparison to active form of vitamin D – 1.25(OH)2D3. In addition, both tested compounds failed to elicit VDR translocation to the nucleus. Thus, it could be postulated that side chain shortening strongly affects binding of analogs to VDR and activation of genomic responses, however do not impair their antiproliferative activities. •VDR active site recognizing 1,3-dihydroxy A-ring of a vitamin D analog is an indispensable fragment required for activity•vitamin D side-chain may not be required for in vitro activity, as truncated analogs retained significant anticancer potential•vitamin D analog with the (5Z,7E) geometry showed much higher potential than the respective (5E,7E) one•PRI-1203 produced moderate induction of CYP24A1 expression, while PRI-1204 showed no effect on the mRNA level for CYP24A1•both, PRI-1203 and PRI-1204 had no effect on the mRNA level neither for CYP2R1, nor for CYP27B in A375 melanoma cells