ritonavir and Leukemia--Myeloid

HIV-1 protease inhibitor, ritonavir (RTV) is a potent inhibitor of cytochrome p450 (CYPs) enzymes. This study explored the effects of RTV on CYP24 which converts 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] to its inactive form 1,24,25,(OH)(3). Real-time RT-PCR showed that exposure of HL-60 cells to 1,25(OH)(2)D(3) induced expression of CYP24, and pre-incubation of these cells with RTV decreased this transcripts, resulting in increased intracellular levels of 1,25(OH)(2)D(3) and potentiation of the ability of 1,25(OH)(2)D(3) to induce growth arrest and differentiation of these cells. Taken together, inhibition of CYP24 might open a new paradigm for therapy using Vitamin D compounds.

Topics: Calcitriol; Cell Differentiation; Cell Proliferation; Down-Regulation; Drug Synergism; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; HIV Protease Inhibitors; HL-60 Cells; Humans; Leukemia, Myeloid; Lipopolysaccharide Receptors; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; Steroid Hydroxylases; Structure-Activity Relationship; Superoxides; Transcription, Genetic; Vitamin D3 24-Hydroxylase

Inhibitors of the protease of human immunodeficiency virus type 1 (HIV-1) may inhibit cytoplasmic retinoic acid-binding proteins, cytochrome P450 isoforms, as well as P-glycoproteins. These features of the protease inhibitors might enhance the activity of retinoids. To explore this hypothesis, myeloid leukemia cells were cultured with all-trans retinoic acid (ATRA) either alone or in combination with the HIV-1 protease inhibitors indinavir, ritonavir, and saquinavir. Consistent with the hypothesis, the HIV-1 protease inhibitors enhanced the ability of ATRA to inhibit growth and induce differentiation 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 cultured with the combination of ATRA and indinavir. Moreover, indinavir enhanced the ability of ATRA to induce expression of the myeloid differentiation-related transcription factor C/EBPepsilon messenger RNA in NB4 cells by 9.5-fold. Taken together, the results show that HIV-1 protease inhibitors enhance the antiproliferative and differentiating effects of ATRA on myeloid leukemia cells. An HIV-1 protease inhibitor might be a useful adjuvant with ATRA for patients with acute promyelocytic leukemia and possibly retinoid-resistant cancers.

Topics: CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Cell Division; Dose-Response Relationship, Drug; HIV Protease Inhibitors; HL-60 Cells; Humans; Immunophenotyping; Indinavir; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Ritonavir; RNA, Messenger; Saquinavir; Tretinoin; Tumor Cells, Cultured