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Article: Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus

TitleBortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus
Authors
Issue Date2013
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/
Citation
Molecular Cancer Therapeutics, 2013, v. 12 n. 5, p. 747-758 How to Cite?
AbstractA novel drug combination of a proteasome inhibitor, bortezomib, and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was tested in nasopharyngeal carcinoma (NPC), both in vitro and in vivo. Dose-response of different concentrations of bortezomib and SAHA on inhibition of cell proliferation of NPCwas determined. Mechanisms of apoptosis and effects on lytic cycle activation of Epstein-Barr virus (EBV) were investigated. Combination of bortezomib and SAHA (bortezomib/SAHA) synergistically induced killing of a panel of NPC cell lines. Pronounced increase in sub-G1, Annexin V-positive, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cell populations were detected after treatment with bortezomib/SAHA when compared with either drug alone. Concomitantly, markedly augmented proteolytic cleavage of PARP, caspase-3, -7, -8, and -9, reactive oxygen species (ROS) generation, and caspase-8-dependent histone acetylation were observed. ROS scavenger, N-acetyl cysteine, diminished the apoptotic effects of bortezomib/SAHA, whereas caspase inhibitor Z-VAD-FMK significantly suppressed the apoptosis without decreasing the generation of ROS. Bortezomib inhibited SAHA's induction of EBV replication and abrogated production of infectious viral particles in NPC cells. Furthermore, bortezomib/SAHA potently induced apoptosis and suppressed the growth of NPC xenografts in nude mice. In conclusion, the novel drug combination of bortezomib and SAHA is highly synergistic in the killing of NPC cells in vitro and in vivo. The major mechanism of cell death is ROS-driven caspase-dependent apoptosis. Bortezomib antagonizes SAHA's activation of EBV lytic cycle in NPC cells. This study provides a strong basis for clinical testing of the combination drug regimen in patients with NPC. ©2013 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/188840
ISSN
2015 Impact Factor: 5.579
2015 SCImago Journal Rankings: 3.224
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHui, KF-
dc.contributor.authorLam, BHW-
dc.contributor.authorHo, DNY-
dc.contributor.authorTsao, GSW-
dc.contributor.authorChiang, AKS-
dc.date.accessioned2013-09-17T14:17:30Z-
dc.date.available2013-09-17T14:17:30Z-
dc.date.issued2013-
dc.identifier.citationMolecular Cancer Therapeutics, 2013, v. 12 n. 5, p. 747-758-
dc.identifier.issn1535-7163-
dc.identifier.urihttp://hdl.handle.net/10722/188840-
dc.description.abstractA novel drug combination of a proteasome inhibitor, bortezomib, and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was tested in nasopharyngeal carcinoma (NPC), both in vitro and in vivo. Dose-response of different concentrations of bortezomib and SAHA on inhibition of cell proliferation of NPCwas determined. Mechanisms of apoptosis and effects on lytic cycle activation of Epstein-Barr virus (EBV) were investigated. Combination of bortezomib and SAHA (bortezomib/SAHA) synergistically induced killing of a panel of NPC cell lines. Pronounced increase in sub-G1, Annexin V-positive, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cell populations were detected after treatment with bortezomib/SAHA when compared with either drug alone. Concomitantly, markedly augmented proteolytic cleavage of PARP, caspase-3, -7, -8, and -9, reactive oxygen species (ROS) generation, and caspase-8-dependent histone acetylation were observed. ROS scavenger, N-acetyl cysteine, diminished the apoptotic effects of bortezomib/SAHA, whereas caspase inhibitor Z-VAD-FMK significantly suppressed the apoptosis without decreasing the generation of ROS. Bortezomib inhibited SAHA's induction of EBV replication and abrogated production of infectious viral particles in NPC cells. Furthermore, bortezomib/SAHA potently induced apoptosis and suppressed the growth of NPC xenografts in nude mice. In conclusion, the novel drug combination of bortezomib and SAHA is highly synergistic in the killing of NPC cells in vitro and in vivo. The major mechanism of cell death is ROS-driven caspase-dependent apoptosis. Bortezomib antagonizes SAHA's activation of EBV lytic cycle in NPC cells. This study provides a strong basis for clinical testing of the combination drug regimen in patients with NPC. ©2013 American Association for Cancer Research.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/-
dc.relation.ispartofMolecular Cancer Therapeutics-
dc.titleBortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus-
dc.typeArticle-
dc.identifier.emailHui, KF: kfhui@hku.hk-
dc.identifier.emailHo, DNY: hodona@hku.hk-
dc.identifier.emailTsao, GSW: gswtsao@hku.hk-
dc.identifier.emailChiang, AKS: chiangak@hku.hk-
dc.identifier.authorityTsao, GSW=rp00399-
dc.identifier.authorityChiang, AKS=rp00403-
dc.identifier.doi10.1158/1535-7163.MCT-12-0811-
dc.identifier.pmid23475956-
dc.identifier.scopuseid_2-s2.0-84877652831-
dc.identifier.hkuros221259-
dc.identifier.volume12-
dc.identifier.issue5-
dc.identifier.spage747-
dc.identifier.epage758-
dc.identifier.isiWOS:000318796400019-
dc.publisher.placeUnited States-

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