Novel Gemini vitamin D3 analogs have potent antitumor activity

The active form of vitamin D-3, 1,25-dillydroxyvitamin D-3 [1,25(OH)(2)D-3], modulates proliferation and induces differentiation of many cancer cells. A new class of analogs of vitamin D3 has been synthesized, having two side-chains attached to carbon-20 (Gemini) and deuterium substituted on one side-chain. We have examined six of these analogs for their ability to inhibit growth of myeloid leukemia (HL-60), prostate (LNCaP, PC-3, DU145), lung (H520), colon (HT-29), and breast (MCF-7) cancer cell lines. Dose-response clonogenic studies showed that all six analogs had greater antiproliferative activities against cancer cells than 1,25(OH)(2)D-3. Although they had similar potency, the most active of these analogs was BXL-01-0120. BXL-01-0120 was 529-fold more potent than 11,25(OH)(2)D-3 3 in causing 50% clonal growth inhibition (ED50) of HL-60 cells. Pulse-exposure studies demonstrated that exposure to BXL-01-120 (10(-9) M, 48 h) resulted in 85% clonal inhibition of HL-60 growth. BXL-01-0120 (10(-11) M, 4 days) induced the differentiation marker, CD11b. Also, morphologically differentiation was more prominent compared to 1,25(OH)(2)D-3. Annexin V assay showed that BXL-01-0120 (10(-10) M, 4 days) induced significantly (p<0.05) more apoptosis than 1,25(OH)(2)D-3. In summary, these analogs have a unique structure resulting in extremely potent inhibition of clonal proliferation of various types of cancer cells, especially HL-60 cells. (C) 2008 Elsevier Ltd. All rights reserved.