Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo.
Rituximab (RTX), a chimeric anti-CD20 antibody, is associated with direct induction of apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) with clinical efficacy in mantle cell lymphoma (MCL). Lenalidomide (LEN), a novel immunomodulatory agent, sensitizes tumor cells and enhances ADCC. Our study attempted to elucidate the mechanism of LEN-enhanced RTX-mediated cytotoxicity of MCL cells. We found that LEN and RTX induced growth inhibition of both cultured and fresh primary MCL cells. LEN enhanced RTX-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Meanwhile, LEN activated NK cells and increased CD16 expression on CD56(low)CD16(+) NK cells. Whole PBMCs but not NK cell-depleted PBMCs treated with LEN augmented 30% of RTX-dependent cytotoxicity. Daily treatment with LEN increased NK cells by 10-folds in SCID mice, and combination of LEN and RTX decreased tumor burden and prolonged survival of MCL-bearing SCID mice. Taken together, our study demonstrates that LEN plus RTX provides a synergistically therapeutic effect on MCL cells by enhancing apoptosis and RTX-dependent NK cell-mediated cytotoxicity and may be an optimal combination in the clinical trial of relapsed or refractory MCL.
Zhang
Liang
L
Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA. liazhang@mdanderson.org
Qian
Zhengzi
Z
Cai
Zhen
Z
Sun
Luhong
L
Wang
Huaqing
H
Bartlett
J Blake
JB
Yi
Qing
Q
Wang
Michael
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001773:Blood Cells / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects; D000077269:Lenalidomide; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D000069283:Rituximab; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D051017:Apoptosis Regulatory Proteins; D000069283:Rituximab; D013792:Thalidomide; D048670:MAP Kinase Kinase 4; D000077269:Lenalidomide