"Tyrosine kinase inhibitor (TKI) therapies which are the first line drugs in chronic myeloid leukemia (CML) have profoundly changed the prognosis of the disease and prolonged survival. However, it is clear that TKI are not able to eradicate efficiently the most primitive leukemic cells, due to their quiescence or oncogene-independence. It would therefore be of major interest to determine if compounds targeting CML progenitors / stem cells can be used in combination with TKI.
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Inecalcitol (19, nor 14 epi 23-yne-1,25 (OH)2D3) (ICC) is a vitamin D3 analog which has been shown to exert antiproliferative effects in several types of experimental tumors. As compared to calcitriol, the active for of natural vitamin D3, ICC has been shown to induce less hypercalcemia in vivo in mice and a higher differentiation inducing effect. The effects of ICC in primary CML progenitors and stem cells has not been tested so far.
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Thus, these results establish that ICC, a clinically used derivative of vitamin D3 has a clear activity in CML progenitors by itself and a major synergistic effect with Imatinib. The combination is not toxic to normal progenitors. This would suggest that ICC could be used in clinical setting, especially if in future experiments, a synergistic effect could be observed with more potent second generation TKI such as Nilotinib and Dasatinib. "
Extrait de Vitamin D3 Analog Inecalcitol Synergizes Vith Imatinib To Inhibit Selectively The Growth Of Chronic Myeloid Leukemia (CML) Progenitors and Stem CellsClinically Relevant Abstract