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Combined proteasome and Bcl‐2 inhibition stimulates apoptosis and inhibits growth in EBV‐transformed lymphocytes: a potential therapeutic approach to EBV‐associated lymphoproliferative diseases
Author(s) -
Srimatkandada Pavani,
Loomis Regina,
Carbone Rocco,
Srimatkandada Srinivasan,
Lacy Jill
Publication year - 2008
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.2008.01044.x
Subject(s) - bortezomib , apoptosis , proteasome inhibitor , cancer research , in vivo , biology , proteasome , in vitro , caspase , caspase 3 , immunology , programmed cell death , microbiology and biotechnology , biochemistry , multiple myeloma
Objectives: Epstein–Barr virus (EBV) transforms B‐cells into immortalized lymphoblastoid cells (LCLs) by triggering signaling pathways that lead to activation of multiple transcription factors and anti‐apoptotic proteins, including NF‐κB and Bcl‐2, respectively. Since proteasome inhibition suppresses NF‐κB activity, we sought to determine whether the proteasome inhibitor, bortezomib, alone or in combination with Bcl‐2 inhibition, has potential as a therapeutic strategy in EBV‐driven B‐cell neoplasms. Methods: We evaluated the effects of bortezomib in LCLs in vitro, in the presence and absence of the small molecular inhibitor of Bcl‐2, HA14‐1, on proliferation, apoptosis, caspase activation, and expression of Bcl‐2 family members, and in vivo in the severe combined immunodeficiency (SCID) model of EBV + lymphoproliferative disease. Results: Bortezomib inhibited proliferation, stimulated apoptosis, and activated caspases‐3 and ‐9 in a dose‐dependent manner in LCLs. In vivo , bortezomib completely abrogated development of EBV + lymphoproliferative disease in LCL‐bearing SCID mice. When HA14‐1 was added to bortezomib in vitro , we observed a synergistic anti‐proliferative effect and enhancement of apoptosis and caspase activation, including activation of caspase‐8, in LCLs. These events were associated with modulation of expression of Bcl‐2 family members towards a pro‐apoptotic profile with translocation of cytochrome C from mitochondria to cytoplasm. Conclusions: These studies demonstrated that bortezomib mediates anti‐tumor effects in EBV‐associated lymphoproliferations both in vitro and in vivo , and that its anti‐proliferative and apoptotic effects are synergistically enhanced in the presence of a Bcl‐2 inhibitor. These findings support further investigation of bortezomib in EBV + lymphoproliferative diseases, and suggest that bortezomib in combination with Bcl‐2 antagonists represents a potential therapeutic strategy for EBV‐driven B‐cell neoplasms