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The combination of bortezomib with enzastaurin or lenalidomide enhances cytotoxicity in follicular and mantle cell lymphoma cell lines
Author(s) -
Cosenza Maria,
Civallero Monica,
Pozzi Samantha,
Marcheselli Luigi,
Bari Alessia,
Sacchi Stefano
Publication year - 2015
Publication title -
hematological oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 44
eISSN - 1099-1069
pISSN - 0278-0232
DOI - 10.1002/hon.2179
Subject(s) - bortezomib , mantle cell lymphoma , protein kinase b , pi3k/akt/mtor pathway , mapk/erk pathway , lenalidomide , cancer research , apoptosis , cell growth , cell cycle , proteasome inhibitor , chemistry , pharmacology , biology , kinase , lymphoma , immunology , microbiology and biotechnology , multiple myeloma , biochemistry
We analyzed the combination of a proteasome inhibitor (bortezomib) with enzastaurin (PKC/AKT‐inhibitor) or lenalidomide (immunomodulatory agent) for the inhibition of proliferation and induction of apoptosis in B‐cell lymphoma cell lines and primary malignant cells. The effects of bortezomib, enzastaurin or lenalidomide, alone or in combinations, on cell viability and apoptosis were evaluated using the Cell Proliferation Kit and flow cytometry analysis. The interaction between drugs was examined by the Chou–Talalay method. Cell cycle analysis was performed by flow cytometry. The PI3K/AKT, PKC and MAPK/ERK signaling pathways were analyzed using western blot. Bortezomib with either enzastaurin or lenalidomide synergistically induced anti‐proliferative and pro‐apoptotic effects in B‐cell lymphoma cells, even in the presence of the bone marrow microenvironment. The direct cytotoxicity is mediated by signaling events involving the PI3K/AKT, PKC and MAPK/ERK pathways leading to cell death. The significant increase of apoptosis was mediated by an increased ratio of pro‐apoptotic proteins (Bax, Bad and Bim) to anti‐apoptotic proteins (Bcl‐2, Bcl‐xL and Mcl‐1), triggering the cleavage of caspases ‐3, ‐9, ‐8 and PARP. Further evaluation of the combination of bortezomib with enzastaurin or lenalidomide for the treatment of B‐cell lymphoma is warranted, with the goal to improve the quality of life and survival of patients. Copyright © 2014 John Wiley & Sons, Ltd.