20-epi-Vitamin D3 Analogues: A Novel Class of Potent Inhibitors of Proliferation and Inducers of Differentiation of Human Breast Cancer Cell Lines

摘要: We have studied the in vitro biological activities and mechanism of action 1,25-dihydroxyvitamin D3 (1,25D3) four potent 1,25D3 analogues [20-epi-22oxa-24a,26a,27a-tri-homo-1,25(OH)2D3 (KH 1060); 20-epi-1,25(OH)2D3; 1,25(OH)2-16ene-D3; 1,25(OH)2-16ene-23yne-D3] on proliferation differentiation estrogen receptor-negative (MDA-MB-436, BT-20, SK-BR-3, MDA-MB-231), receptor-weakly positive (BT474), receptor-positive (MCF-7) breast cancer cell lines. Dose-response studies showed that KH 1060 was most analogue, because it able to induce all seven lines (measured by lipid staining) suppress more than 50% clonal (ED50) at 10(-10) M lines, except MDA-MB-436 BT-20. To explore how these compounds mediated antiproliferative actions, their effects cycle, expression bcl-2 p53, apoptosis were assessed. Five six a mutant p53 gene, whereas MCF-7 has wild-type p53. Immunohistochemical staining protein predominantly localized nucleus each for MCF-7, which expressed cytoplasm. After incubation with (3 days; 10(-7) M), as determined immunohistochemical localization markedly decreased BT-474, MDA-MB-231; same cells profoundly inhibited arrested G0/G1 phase cycle when cultured 1060. In contrast, BT-20 refractory effect (ED50 < 10(-6) M) had no down-regulation changes after exposure morphological DNA fragmentation, indicative 48 h (10(-6) during time accumulated detected three other (MDA-MB-231, BT-474) mutated conclusion, data indicate is an extremely analogue inducing potently inhibiting growth them concomitant arrest G0/G1.(ABSTRACT TRUNCATED AT 400 WORDS)