Synergistic Induction of HL60 Cell Differentiation by Ketoconazole and 1-Desoxy Analogues of Vitamin D3

Authors:
  • JGJeffrey P. Gardner
    Jeffrey P. Gardner
  • AKAhmed Kheir
    Ahmed Kheir
  • MUMilan R. Uskokovic
    Milan R. Uskokovic
  • GSGeorge P. Studzinski
    George P. Studzinski
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Abstract
Background: The goal of differentiation therapy is to induce cancer cells to stop proliferating and to express characteristics of normal cells. Vitamin D analogues, such as the deltanoids, are being evaluated as differentiation agents in the treatment of several human cancers (e.g., myeloid leukemias); however, these compounds have a tendency to produce hypercalcemia in patients receiving therapy. A combination of a differentiation-inducing deltanoid with a compound that blocks entry of calcium into cells (e.g., ketoconazole) may offer a new approach to differentiation therapy and address the problem of hypercalcemia. We investigated whether various ketoconazole—deltanoid combinations would alter cellular differentiation or intracellular calcium homeostasis in comparison with deltanoids used alone. Methods: Cultured human leukemia HL60 cells were treated with ketoconazole—deltanoid combinations. Markers of differentiation (expression of CD11b and CD14 antigens and of non-specific esterase) were measured by flow cytometry and cytochemistry; cell cycle distribution was measured by flow cytometry of propidium iodide-stained cells. Expression of differentiation-related genes was assessed by northern blotting and immunoblotting, and changes in intracellular calcium homeostasis were monitored by fluorescence analysis of fura-2-containing cells. Results: Ketoconazole strongly potentiated the differentiating activity of the deltanoids, which exhibited low potency when used alone. Ketoconazole—deltanoid combinations had little effect on HL60 cell-cycle distribution, although the cells did stop proliferating and they differentiated. Ketoconazole—deltanoid combinations produced only minor changes in intracellular calcium homeostasis compared with changes produced by 1,25-dihydroxyvitamin D3, either alone or in combination with ketoconazole. Conclusion: These results suggest that ketoconazole may be useful in combination with vitamin D analogues in the differentiation therapy for myeloid leukemias.

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