Lenalidomide synergizes with dexamethasone to induce growth arrest and apoptosis of mantle cell lymphoma cells in vitro and in vivo.
Mantle cell lymphoma (MCL) frequently relapses after therapy and new therapeutic regimens are needed. Lenalidomide (LEN), a thalidomide analogue, displays direct cytotoxicity against MCL cells. This study was undertaken to evaluate the combined therapeutic effect of LEN and dexamethasone (DEX) on MCL. LEN synergized with DEX to induce the growth inhibition and apoptosis of both established MCL cells and freshly isolated MCL cells from refractory or relapsed MCL patients. The synergy was more significant in freshly isolated patients' MCL cells than established MCL cells. Cell cycle analysis showed that LEN enhanced DEX-induced G(0)/G(1) arrest. The effect of the LEN and DEX combination on apoptotic induction was mainly through mitochondrial signaling pathways, as demonstrated by phosphorylation of bcl-2 and up-regulation of proapoptotic proteins Bax, Bad and Bim, and the subsequent activation of caspase-9, caspase-3, and cleavage of PARP. Importantly, the combination of LEN and DEX delayed the tumor growth and improved the survival of MCL-bearing mice. The results support the use of the LEN and DEX combination as a new therapeutic regimen in clinical trials of MCL.
Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Zhengzi
Z
Qian
Liang
L
Zhang
Zhen
Z
Cai
Luhong
L
Sun
Huaqing
H
Wang
Qing
Q
Yi
Michael
M
Wang
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003907:Dexamethasone / Q000008:administration & dosage; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D000077269:Lenalidomide; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide