title: mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells.
abstract: High activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis in pre-B-cell acute lymphoblastic leukemia (B-ALL), suggesting that inhibiting mTOR might be clinically useful. However, emerging data indicate that mTOR inhibitors are most effective when combined with other target agents. One strategy is to combine with histone deacetylase (HDAC) inhibitors, since B-ALL is often characterized by epigenetic changes that silence the expression of pro-apoptotic factors. Here we tested combinations of mTOR and pan-HDAC inhibitors on B-ALL cells, including both Philadelphia chromosome-positive (Ph+) and non-Ph cell lines. We found that mTOR kinase inhibitors (TOR-KIs) synergize with HDAC inhibitors to cause apoptosis in B-ALL cells and the effect is greater when compared to rapamycin plus HDAC inhibitors. The combination of TOR-KIs with the clinically approved HDAC inhibitor vorinostat increased apoptosis in primary pediatric B-ALL cells in vitro. Mechanistically, TOR-KI and HDAC inhibitor combinations increased expression of pro-death genes, including targets of the Forkhead Box O (FOXO) transcription factors, and increased sensitivity to apoptotic triggers at the mitochondria. These findings suggest that targeting epigenetic factors can unmask the cytotoxic potential of TOR-KIs towards B-ALL cells.
authors.affiliation: Department of Molecular Biology & Biochemistry, University of California, Irvine, CA.
authors.forename: Brandon R
authors.initials: BR
authors.lastname: Beagle
authors.affiliation: Department of Molecular Biology & Biochemistry, University of California, Irvine, CA.
authors.forename: Duc M
authors.initials: DM
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Biology & Biochemistry, University of California, Irvine, CA.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Mallya
authors.affiliation: Department of Molecular Biology & Biochemistry, University of California, Irvine, CA.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Tang
authors.affiliation: Department of Molecular Biology & Biochemistry, University of California, Irvine, CA.
authors.forename: Mengrou
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.|Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.|Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Department of Molecular Biology & Biochemistry, University of California, Irvine, CA.
authors.forename: Thanh-Trang
authors.initials: TT
authors.lastname: Vo
authors.affiliation: Department of Molecular Biology & Biochemistry, University of California, Irvine, CA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D053181:Caspase 8; D006655:Histone Deacetylases