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Combination of SAHA and bortezomib up‐regulates CDKN2A and CDKN1A and induces apoptosis of Epstein‐Barr virus‐positive Wp‐restricted Burkitt lymphoma and lymphoblastoid cell lines
Author(s) -
Hui Kwai Fung,
Leung Yvonne Y.,
Yeung Po L.,
Middeldorp Jaap M.,
Chiang Alan K.S.
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13089
Subject(s) - bortezomib , apoptosis , cancer research , proteasome inhibitor , cell culture , epstein–barr virus , granzyme b , biology , romidepsin , burkitt's lymphoma , in vivo , lymphoma , chemistry , microbiology and biotechnology , histone deacetylase , immunology , virus , immune system , multiple myeloma , histone , cd8 , biochemistry , genetics , gene
Summary Epstein‐Barr virus (EBV) latent proteins exert anti‐apoptotic effects on EBV‐transformed lymphoid cells by down‐regulating BCL2L11 (BIM), CDKN2A (p16 INK4A ) and CDKN1A (p21 WAF1 ). However, the potential therapeutic effects of targeting these anti‐apoptotic mechanisms remain unexplored. Here, we tested both in vitro and in vivo effects of the combination of histone deacetylase (HDAC) and proteasome inhibitors on the apoptosis of six endemic Burkitt lymphoma (BL) lines of different latency patterns (types I and III and Wp‐restricted) and three lymphoblastoid cell lines (LCLs). We found that the combination of HDAC and proteasome inhibitors (e.g. SAHA/bortezomib) synergistically induced the killing of Wp‐restricted and latency III BL and LCLs but not latency I BL cells. The synergistic killing was due to apoptosis, as evidenced by the high percentage of annexin V positivity and strong cleavage of PARP1 (PARP) and CASP3 (caspase‐3). Concomitantly, SAHA/bortezomib up‐regulated the expression of CDKN2A and CDKN1A but did not affect the level of BCL2L11 or BHRF1 (viral homologue of BCL2). The apoptotic effects were dependent on reactive oxygen species generation. Furthermore, SAHA/bortezomib suppressed the growth of Wp‐restricted BL xenografts in nude mice. This study provides the rationale to test the novel application of SAHA/bortezomib on the treatment of EBV‐associated Wp‐restricted BL and post‐transplant lymphoproliferative disorder.