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-kappaB and Bcl-2, respectively. Since proteasome inhibition suppresses NF-kappaB 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.
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-kappaB and Bcl-2, respectively. Since proteasome inhibition suppresses NF-kappaB 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 SCIDmice. 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.
Authors: Suleyman Serdar Koca; Metin Ozgen; Ferda Dagli; Mehmet Tuzcu; Ibrahim Hanifi Ozercan; Kazim Sahin; Ahmet Isik Journal: Inflammation Date: 2012-06 Impact factor: 4.092
Authors: Kalavathi Dasuri; Philip J Ebenezer; Le Zhang; Sun Ok Fernandez-Kim; Romina M Uranga; Elena Gavilán; Alessia Di Blasio; Jeffrey N Keller Journal: Free Radic Biol Med Date: 2010-08-01 Impact factor: 7.376