title: Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression.
abstract: When grown in 3D cultures as spheroids, mesothelioma cells acquire a multicellular resistance to apoptosis that resembles that of solid tumors. We have previously found that resistance to the proteasome inhibitor bortezomib in 3D can be explained by a lack of upregulation of Noxa, the pro-apoptotic BH3 sensitizer that acts via displacement of the Bak/Bax-activator BH3-only protein, Bim. We hypothesized that the histone deacetylase inhibitor vorinostat might reverse this block to Noxa upregulation in 3D. Indeed, we found that vorinostat effectively restored upregulation of Noxa protein and message and abolished multicellular resistance to bortezomib in the 3D spheroids. The ability of vorinostat to reverse resistance was ablated by knockdown of Noxa or Bim, confirming the essential role of the Noxa/Bim axis in the response to vorinostat. Addition of vorinostat similarly increased the apoptotic response to bortezomib in another 3D model, the tumor fragment spheroid, which is grown from human mesothelioma ex vivo. In addition to its benefit when used with bortezomib, vorinostat also enhanced the response to cisplatin plus pemetrexed, as shown in both 3D models. Our results using clinically relevant 3D models show that the manipulation of the core apoptotic repertoire may improve the chemosensitivity of mesothelioma. Whereas neither vorinostat nor bortezomib alone has been clinically effective in mesothelioma, vorinostat may undermine chemoresistance to bortezomib and to other therapies thereby providing a rationale for combinatorial strategies.
authors.affiliation: Lung Biology Center, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America. dario.barbone@ucsf.edu
authors.forename: Dario
authors.initials: D
authors.lastname: Barbone
authors.forename: Priscilla
authors.initials: P
authors.lastname: Cheung
authors.forename: Sailaja
authors.initials: S
authors.lastname: Battula
authors.forename: Sara
authors.initials: S
authors.lastname: Busacca
authors.forename: Steven G
authors.initials: SG
authors.lastname: Gray
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.forename: David J
authors.initials: DJ
authors.lastname: Sugarbaker
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
authors.forename: V Courtney
authors.initials: VC
authors.lastname: Broaddus
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D008654:Mesothelioma; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000068437:Pemetrexed; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids; D005971:Glutamates; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D000068437:Pemetrexed; D000077337:Vorinostat; D006147:Guanine; D000069286:Bortezomib; D002945:Cisplatin