title: The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy.
abstract: We analyzed the cellular and molecular effects of two different histone deacetylase inhibitors (HDACi), MGCD0103 and vorinostat, in combination with GX15-070, a BH3-mimetic, in acute myeloid leukemia (AML) cell lines and primary AML cells, and demonstrated that the combination has a synergistic antileukemia effect. We observed that in addition to apoptosis, autophagy also accounts for the observed nonapoptotic decrease of cell viability. Mechanistically, we established a role for calpain activity and ER-located caspase signaling in the induction of both autophagy and apoptosis following this combination of drugs. These findings reveal that for this specific combination, autophagy plays a positive role in inducing cytotoxicity, and that the involved ER signaling networks, as well as their clinical relevance, should be further studied in both preclinical and clinical trials of leukemia and other malignancies.
authors: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Yue
authors: Y
authors: Wei
authors: Tapan
authors: T
authors: Kadia
authors: Weigang
authors: W
authors: Tong
authors: Ming
authors: M
authors: Zhang
authors: Yu
authors: Y
authors: Jia
authors: Hui
authors: H
authors: Yang
authors: Yumin
authors: Y
authors: Hu
authors: Jean
authors: J
authors: Viallet
authors: Susan
authors: S
authors: O'Brien
authors: Guillermo
authors: G
authors: Garcia-Manero
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D000077337:Vorinostat
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D000077337:Vorinostat; C523184:mocetinostat; C520962:obatoclax