HIV-1 protease inhibitors decrease proliferation and induce differentiation of human myelocytic leukemia cells

Inhibitors of the protease of human immunodeficiency virus type 1 (HIV-1) m ay inhibit cytoplasmic retinoic acid-binding proteins, cytochrome P450 isof orms, as well as P-glycoproteins, These features of the protease inhibitors might enhance the activity of retinoids, To explore this hypothesis, myelo id leukemia cells were cultured with all-trans retinoic acid (ATRA) either alone or in combination with the HIV-I protease inhibitors indinavir, riton avir, and saquinavir, Consistent with the hypothesis, the HIV-1 protease in hibitors enhanced the ability of ATRA to inhibit growth and induce differen tiation of HL-60 and NB4 myeloid leukemia cells, as measured by expression of CD11b and CD66b cell surface antigens, as well as reduction of nitroblue tetrazolium. Growth of ATRA-resistant UF-1 cells was also inhibited when c ultured with the combination of ATRA and indinavir, Moreover, indinavir enh anced the ability of ATRA to induce expression of the myeloid differentiati on-related transcription factor C/EBP epsilon messenger RNA in NB4 cells by 9.5-fold. Taken together, the results show that HIV-I protease inhibitors enhance the antiproliferative and differentiating effects of ATRA on myeloi d leukemia cells. An HIV-1 protease inhibitor might be a useful adjuvant wi th ATRA for patients with acute promyelocytic leukemia and possibly retinoi d-resistant cancers. (C) 2000 by The American Society of Hematology.