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Conference Paper: Suberoylanilide Hydroxamic Acid and Bortezomib Synergistically Induce Apoptosis of EBV-Positive Burkitt Lymphoma Cells of Wp-Restricted or Type III Latency

TitleSuberoylanilide Hydroxamic Acid and Bortezomib Synergistically Induce Apoptosis of EBV-Positive Burkitt Lymphoma Cells of Wp-Restricted or Type III Latency
Authors
Issue Date2014
PublisherHong Kong College of Paediatricians. The Journal's web site is located at http://www.hkjpaed.org/index.asp
Citation
The Annual Scientific Meeting of the Hong Kong College of Paediatricians, Hong Kong, China, 7 December 2013. In the Hong Kong Journal of Paediatrics (New series), 2014, v. 19 n. 2, p. 118 How to Cite?
AbstractBackground: Endemic Burkitt lymphoma (BL) is strongly associated with Epstein-Barr virus (EBV) with variable latent viral gene expression patterns (type I, Wprestricted and type III latency). We reported that bortezomib, a proteasome inhibitor, could potentiate the anti-tumour effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on EBV-positive nasopharyngeal carcinoma. Here, we aim to investigate the anti-tumour effects of SAHA, bortezomib and combination of the two drugs on EBV-positive BL cells of different viral latency. Methods: Cytotoxic effect of SAHA, bortezomib or combination of the two drugs (SAHA/bort) on BL cells of type I, Wp-restricted or type III latency was determined by MTT assay. Effects on apoptosis and cell cycle were measured by flow cytometry. Expression of apoptotic markers, EBV latent proteins and tumour suppressor genes were analyzed by western blotting. Results: BL cells of Wp-restricted or type III latency, which express the EBV nuclear antigen (EBNA)-3 proteins, were more resistant to killing by SAHA than those of type I latency. However, adding bortezomib to SAHA synergistically enhanced the killing of BL cells of these two latency types. Compared with SAHA or bortezomib, SAHA/bort triggered enhanced apoptosis in the BL cells as indicated by the higher percentages of AV/PI-positive and sub-G1 populations as well as stronger proteolytic cleavage of apoptotic markers, PARP, caspase-3 and caspase-9, and induced the expression of two tumour suppressor genes, p16INK4A and p21WAF1, which are known to be down-regulated by the EBNA3 proteins. Furthermore, SAHA/bort suppressed the growth of BL xenografts in nude mice. Conclusions: Combination of SAHA and bortezomib synergistically induces the apoptosis of BL cells of Wprestricted or type III latency and possibly overcomes the resistance to apoptosis conferred by the EBNA3 proteins by up-regulation of p16INK4A and p21WAF1 genes. Clinical application of this drug combination to the treatment of primary EBV-driven lymphoproliferative disease such as post-transplant lymphoproliferative disorder should be further explored.
DescriptionThe abstract can be viewed at: http://www.hkjpaed.org/pdf/2014;19;100-128.pdf
Persistent Identifierhttp://hdl.handle.net/10722/196817
ISSN
2015 Impact Factor: 0.194
2015 SCImago Journal Rankings: 0.123

 

DC FieldValueLanguage
dc.contributor.authorHui, KFen_US
dc.contributor.authorLeung, YYen_US
dc.contributor.authorYeung, PLen_US
dc.contributor.authorChiang, AKSen_US
dc.date.accessioned2014-04-29T03:43:53Z-
dc.date.available2014-04-29T03:43:53Z-
dc.date.issued2014en_US
dc.identifier.citationThe Annual Scientific Meeting of the Hong Kong College of Paediatricians, Hong Kong, China, 7 December 2013. In the Hong Kong Journal of Paediatrics (New series), 2014, v. 19 n. 2, p. 118en_US
dc.identifier.issn1013-9923-
dc.identifier.urihttp://hdl.handle.net/10722/196817-
dc.descriptionThe abstract can be viewed at: http://www.hkjpaed.org/pdf/2014;19;100-128.pdf-
dc.description.abstractBackground: Endemic Burkitt lymphoma (BL) is strongly associated with Epstein-Barr virus (EBV) with variable latent viral gene expression patterns (type I, Wprestricted and type III latency). We reported that bortezomib, a proteasome inhibitor, could potentiate the anti-tumour effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on EBV-positive nasopharyngeal carcinoma. Here, we aim to investigate the anti-tumour effects of SAHA, bortezomib and combination of the two drugs on EBV-positive BL cells of different viral latency. Methods: Cytotoxic effect of SAHA, bortezomib or combination of the two drugs (SAHA/bort) on BL cells of type I, Wp-restricted or type III latency was determined by MTT assay. Effects on apoptosis and cell cycle were measured by flow cytometry. Expression of apoptotic markers, EBV latent proteins and tumour suppressor genes were analyzed by western blotting. Results: BL cells of Wp-restricted or type III latency, which express the EBV nuclear antigen (EBNA)-3 proteins, were more resistant to killing by SAHA than those of type I latency. However, adding bortezomib to SAHA synergistically enhanced the killing of BL cells of these two latency types. Compared with SAHA or bortezomib, SAHA/bort triggered enhanced apoptosis in the BL cells as indicated by the higher percentages of AV/PI-positive and sub-G1 populations as well as stronger proteolytic cleavage of apoptotic markers, PARP, caspase-3 and caspase-9, and induced the expression of two tumour suppressor genes, p16INK4A and p21WAF1, which are known to be down-regulated by the EBNA3 proteins. Furthermore, SAHA/bort suppressed the growth of BL xenografts in nude mice. Conclusions: Combination of SAHA and bortezomib synergistically induces the apoptosis of BL cells of Wprestricted or type III latency and possibly overcomes the resistance to apoptosis conferred by the EBNA3 proteins by up-regulation of p16INK4A and p21WAF1 genes. Clinical application of this drug combination to the treatment of primary EBV-driven lymphoproliferative disease such as post-transplant lymphoproliferative disorder should be further explored.en_US
dc.languageengen_US
dc.publisherHong Kong College of Paediatricians. The Journal's web site is located at http://www.hkjpaed.org/index.asp-
dc.relation.ispartofHong Kong Journal of Paediatrics (New series)en_US
dc.titleSuberoylanilide Hydroxamic Acid and Bortezomib Synergistically Induce Apoptosis of EBV-Positive Burkitt Lymphoma Cells of Wp-Restricted or Type III Latencyen_US
dc.typeConference_Paperen_US
dc.identifier.emailHui, KF: kfhui@hku.hken_US
dc.identifier.emailChiang, AKS: chiangak@hku.hken_US
dc.identifier.authorityChiang, AKS=rp00403en_US
dc.identifier.hkuros228726en_US
dc.identifier.hkuros238375-
dc.identifier.volume19-
dc.identifier.issue2-
dc.identifier.spage118-
dc.identifier.epage118-
dc.publisher.placeChina-

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