title: Combination with vorinostat overcomes ABT-263 (navitoclax) resistance of small cell lung cancer.
abstract: Small cell lung cancer (SCLC) is an aggressive tumor type with high mortality. One promising approach for SCLC treatment would be to utilize agents targeting molecular abnormalities regulating resistance to apoptosis. BH3 mimetic antagonists, such as ABT-737 and its orally available derivative ABT-263 (navitoclax) have been developed to block the function of pro-survival BCL-2 family members. The sensitivity of SCLC to these drugs varies over a broad range in vitro and in clinical trials. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is a critical determinant of sensitivity to ABT-737. Thus, pharmacological up-regulation of Noxa could enhance cell death induced by the BH3 mimetics. We find that the combination of ABT-263 and a HDAC inhibitor, vorinostat, efficiently induces apoptosis in a variety of SCLC cell lines, including ABT-263 resistant cell lines. Cell death induced by combined treatment is Noxa- and/or BIM-dependent in some cell lines but in others appears to be mediated by down-regulation of BCL-XL and release of BAK from BCL-XL and MCL-1. These results suggest that combination of HDAC inhibitors and BCL-2 inhibitors could be an alternative and effective regimen for SCLC treatment.
authors.affiliation: a Department of Oral and Craniofacial Molecular Biology , School of Dentistry, Massey Cancer Center, Virginia Commonwealth University , Richmond , Virginia , USA.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nakajima
authors.affiliation: a Department of Oral and Craniofacial Molecular Biology , School of Dentistry, Massey Cancer Center, Virginia Commonwealth University , Richmond , Virginia , USA.
authors.forename: Kanika
authors.initials: K
authors.lastname: Sharma
authors.affiliation: a Department of Oral and Craniofacial Molecular Biology , School of Dentistry, Massey Cancer Center, Virginia Commonwealth University , Richmond , Virginia , USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hicks
authors.affiliation: a Department of Oral and Craniofacial Molecular Biology , School of Dentistry, Massey Cancer Center, Virginia Commonwealth University , Richmond , Virginia , USA.
authors.forename: Ngoc
authors.initials: N
authors.lastname: Le
authors.affiliation: a Department of Oral and Craniofacial Molecular Biology , School of Dentistry, Massey Cancer Center, Virginia Commonwealth University , Richmond , Virginia , USA.
authors.forename: Rikiara
authors.initials: R
authors.lastname: Brown
authors.affiliation: b Department of Internal Medicine , Virginia Commonwealth University, McGuire Veterans Affairs Medical Center , Richmond , Virginia , USA.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Krystal
authors.affiliation: a Department of Oral and Craniofacial Molecular Biology , School of Dentistry, Massey Cancer Center, Virginia Commonwealth University , Richmond , Virginia , USA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Harada
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage*; D000077337:Vorinostat; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D000814:Aniline Compounds; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D000077337:Vorinostat; C528561:navitoclax
keywords: ABT-263; BCL-2 family; BCL-XL; Noxa; apoptosis; small cell lung cancer; vorinostat