title: Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells.
abstract: Hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activity against human acute leukemia. Here we describe HA-HDI-resistant human acute myeloid leukemia (AML) HL-60 (HL-60/LR) cells that are resistant to LAQ824, vorinostat, LBH589, and sodium butyrate. HL-60/LR cells show increased expression of HDACs 1, 2, and 4 but lack HDAC6 expression, with concomitant hyperacetylation of heat shock protein 90 (hsp90). Treatment with HA-HDI failed to further augment hsp90 acetylation, or increase the levels of p21 or reactive oxygen species (ROSs), in HL-60/LR versus HL-60 cells. Although cross-resistant to antileukemia agents (eg, cytarabine, etoposide, and TRAIL), HL-60/LR cells are collaterally sensitive to the hsp90 inhibitor 17-AAG. Treatment with 17-AAG did not induce hsp70 or deplete the hsp90 client proteins AKT and c-Raf. HL-60/LR versus HL-60 cells display a higher growth fraction and shorter doubling time, along with a shorter interval to generation of leukemia and survival in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, resistance of AML cells to HA-HDIs is associated with loss of HDAC6, hyperacetylation of hsp90, aggressive leukemia phenotype, and collateral sensitivity to 17-AAG. These findings suggest that an hsp90 inhibitor-based antileukemia therapy may override de novo or acquired resistance of AML cells to HA-HDIs.
authors.affiliation: MCG Cancer Center, Medical College of Georgia, Augusta, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Rekha
authors.initials: R
authors.lastname: Rao
authors.forename: Pravina
authors.initials: P
authors.lastname: Fernandez
authors.forename: Bryan
authors.initials: B
authors.lastname: Herger
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Yang
authors.forename: Jianguang
authors.initials: J
authors.lastname: Chen
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kolhe
authors.forename: Aditya
authors.initials: A
authors.lastname: Mandawat
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Wang
authors.forename: Rajeshree
authors.initials: R
authors.lastname: Joshi
authors.forename: Kelly
authors.initials: K
authors.lastname: Eaton
authors.forename: Pearl
authors.initials: P
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Stephen
authors.initials: S
authors.lastname: Peiper
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D000076249:Heat Shock Transcription Factors; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D009363:Neoplasm Proteins / Q000378:metabolism; D000077767:Panobinostat; D016196:S Phase / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C477361:LAQ824; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; D014157:Transcription Factors; D014404:Tubulin; C112765:tanespimycin; D000077337:Vorinostat; D000077209:Decitabine; D000077767:Panobinostat; D001374:Azacitidine