Inhibition of cytochrome P-450 modulates all-trans-retinoic acid-induced differentiation and apoptosis of HL-60 cells

We studied the effects of inhibition of cytochrome P-450 by proadifen (SKF5 25A) on the processes induced in myeloid leukemia HL-60 cells by all-trans- retinoic acid (ATRA). The parameters reflecting cell proliferation, differe ntiation, and apoptosis were detected by flow cytometry as the principal me thod at selected time intervals (24-96 hours). Changes in the expression of Bcl-2 protein were detected by Western blotting. The majority of experimen ts were designed as a factorial combination of the treatment and assessed f or significance of the interactions. Proadifen was demonstrated synergistic ally (1) to potentiate the antiproliferative and differentiation effects of ATRA, and (2) to increase cell viability and prevent ATRA-induced apoptosi s. Moreover, proadifen weakened ATRA-induced downregulation of the Bcl-2 pr otein. Our results may be of practical importance because cytochrome P-450 inhibitors are used clinically in treating cancer patients. Assuming that e ffects on the leukemic cells in vivo would be similar, this type of combine d therapy could help to achieve better results even with lower doses of ATR A.