title: HIV-1 protease inhibitors decrease proliferation and induce differentiation of human myelocytic leukemia cells.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Infectious Disease, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ikezoe
authors.forename: E S
authors.initials: ES
authors.lastname: Daar
authors.forename: J
authors.initials: J
authors.lastname: Hisatake
authors.forename: H
authors.initials: H
authors.lastname: Taguchi
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D016130:Immunophenotyping; D019469:Indinavir / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D014212:Tretinoin; D019469:Indinavir; D019258:Saquinavir; D019438:Ritonavir