期刊
BLOOD
卷 115, 期 22, 页码 4478-4487出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-12-257261
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资金
- National Institutes of Health [CA63753, CA93738, CA100866]
- Leukemia & Lymphoma Society of America [R6059-06]
- Multiple Myeloma Research Foundation
- V Foundation
- Lymphoma SPORE [1P50 CA130805]
Interactions between histone deacetylase inhibitors (HDACIs) and the novel proteasome inhibitor carfilzomib (CFZ) were investigated in GC-and activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) cells. Coadministration of subtoxic or minimally toxic concentrations of CFZ) with marginally lethal concentrations of HDACIs (vorinostat, SNDX-275, or SBHA) synergistically increased mitochondrial injury, caspase activation, and apoptosis in both GC- and ABC-DLBCL cells. These events were associated with Jun NH2-terminal kinase (JNK) and p38MAPK activation, abrogation of HDACI-mediated nuclear factor-kappa B activation, AKT inactivation, Ku70 acetylation, and induction of gamma H2A.X. Genetic or pharmacologic JNK inhibition significantly diminished CFZ/vorinostat lethality. CFZ/vorinostat induced pronounced lethality in 3 primary DLBCL specimens but minimally affected normal CD34(+) hematopoietic cells. Bortezomib-resistant GC (SUDHL16) and ABC (OCI-LY10) cells exhibited partial cross-resistance to CFZ. However, CFZ/vorinostat dramatically induced resistant cell apoptosis, accompanied by increased JNK activation and gamma H2A.X expression. Finally, subeffective vorinostat doses markedly increased CFZ-mediated tumor growth suppression and apoptosis in a murine xenograft OCI-LY10 model. These findings indicate that HDACIs increase CFZ activity in GC- and ABC-DLBCL cells sensitive or resistant to bortezomib through a JNK-dependent mechanism in association with DNA damage and inhibition of nuclear factor-kappa B activation. Together, they support further investigation of strategies combining CFZ and HDACIs in DLBCL. (Blood. 2010; 115(22): 4478-4487)
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