Enhancement of chemical-carcinogen-induced cell transformation in hamster embryo cells by 1α,25-dihydroxycholecalciferol, the biologically active metabolite of vitamin D3

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Abstract
The biologically active metabolite of vitamin D3, 1α,25-dihydroxycholecalciferol [1,25-(OH)2D3], which by itself was not effective in inducing morphological cell transformation in vitro in the Syrian hamster embryo colony assay, enhanced such a transformation in a dose-dependent manner in cells pretreated with a series of known chemical carcinogens. Treatment of the hamster embryo cells with either benzo[a]pyrene (B[a]P), (±)7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, or N-methyl-N' -nitro-N-nitrosoguanidine for 3 days (stage 1) followed by treatment with 1,25-(OH)2D3 for 4 days (stage 2) increased the transformation frequency compared to the transformation frequency for cells treated with the carcinogen only. Reversing the order of the treatment (i.e., incubating the cells with 1,25-(OH)2D3 prior to B[a]P treatment) did not result in an effective enhancement. Vitamin D3 and 24,25-dihydroxycholecalciferol, another metabolite of this vitamin, also enhanced the frequency of cell transformation but to a lesser degree than did 1,25-(OH)2D3. Pyrene, which is not a carcinogen, did not induce transformed colonies either by itself or when combined with 1,25-(OH)2D3. Benzo[e]pyrene (B[e]P), which is not considered to be a complete carcinogen but can act as a tumor initiator, also was not effective by itself. However, in the two-stage protocol with 1,25-(OH)2D3, B[e]P did induce transformed colonies. Comparison of the enhancing effect of 1,25-(OH)2D3 to that of phorbol-12-myristate-13-acetate (PMA), a known tumor promoter, revealed a heterogeneity in the response to these agents. A high or low responsiveness of the cells to 1,25-(OH)2D3 was not necessarily indicative of a similar responsiveness to PMA. These results indicate that 1,25-(OH)2D3 can act as a promoter of cell transformation in fibroblasts and perhaps other cell types but through a mechanism not necessarily identical to that involving PMA.