Novel Gemini vitamin D3 analogs have potent antitumor activity

The active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 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)2D3. Although they had similar potency, the most active of these analogs was BXL-01-0120. BXL-01-0120 was 529-fold more potent than 1,25(OH)2D3 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)2D3. Annexin V assay showed that BXL-01-0120 (10−10 M, 4 days) induced significantly (p < 0.05) more apoptosis than 1,25(OH)2D3. 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.