Lenalidomide In The Treatment Of Mantle Cell Lymphoma And Its Action Mechanism

Mantle cell lymphoma (MCL) is a challenging B-cell lymphoma to treat,with anaggressive clinical course and extremely poor prognosis.It accounts forapproximately 2.8-6% of all non-Hodgkin's lymphomas (NHLs) and has distinctmorphologic,immunophenotypic,and cytogenetic features,characterized by thet(11;14) (q13;q32) translocation resulting in cyclin D1 overexpression and cell-cycledysregulation.Although MCL patients achieve a high rate of complete response fromfrontline therapies,but relapse almost always occurs with a median overall survival of3-4 years with less than 15% of patients alive at 5 years.Therefore,MCL remainsincurable and novel targeted agents and immunotherapies with improved efficacy andsafety are urgently required to improve the survival of patients with MCL.LEN,a novel anticancer drug,has emerged as a potent treatment with improvedsafety profile for multiple myeloma (MM) and received FDA approval for use incombination with DEX in relapsed or refractory MM patients.Although the exactmechanism of its action remains complicated and unclear,LEN has been shown invarious systems to have striking antitumor activities directly targeting tumor cells andtheir microenvironment.The success of LEN in the treatment of MM has led to itsexpanded use in treating other B-cell malignancies,with impressive results in someNHLs.These encouraging findings prompted us to investigate the therapeuticeffeicacy of LEN alone or in combination on MCL cells and attempt to elucidate itsantitumor mechanism.Our study could provide favorable preclinical data for thefuture use of LEN-containing regimens in clinical trials of MCL.Partâ… Lenalidomide plus dexamethasone induces the growth arrestand apoptosis of mantle cell lymphoma cells in vitro and in vivoObjective Our study was undertaken to evaluate the effect of LEN combined withDEX on MCL cells and elucidate the mechanism by which it induces tumor cellapoptosis.Methods Established MCL cells and freshly isolated MCL cells from three relapsedpatients were treated with LEN,DEX individually or in combination of two drugs (LEN/DEX).Cell proliferation,cell cycle distribution and apoptosis were evaluatedto determine if there was additive or synergistic effect of LEN/DEX regimen.Westernblot analysis was used to elucidate the molecular mechanism by which different druginduced apoptosis in MCL cells.In addition,a MCL-bearing xenograft model insevere combined immune deficiency (SCID) mice was established to examine the invivo efficacy of the regimen to eradicate MCL cells.Results The results showed that LEN and DEX induced growth inhibition andapoptosis of MCL cell lines and freshly isolated patient MCL cells in adose-dependent manner.Cell cycle analysis showed that LEN was able to enhanceDEX-induced G₀/G₁ arrest despite no effect using LEN alone.Apoptosis induced byLEN/DEX was revealed mainly through mitochondrial pathways,as demonstrated byup-regulation of proapoptotic proteins phosphor-Bcl-2,Bax,and Bad,and thesubsequent cleavage of caspase-9,caspase-3,and PARP;This effect was moresignificant in primary MCL cells than established MCL cells.Importantly,LEN/DEXwas also effective to delay tumor growth and improve survival of MCL-bearing SCIDmice inoculated subcutaneously with 1×10⁷ MCL cells.Conclusions LEN/DEX inhibits growth and induces apoptosis of MCL cells invitro and in vivo.Cell apoptosis was induced mainly through mitochondrial pathway.Our results provide favorable preclinical data for the future use of LEN/DEX regimenin clinical trials of MCL.Partâ…¡Dual mechanisms for lenalidomide-enhanced rituximab-mediated killing of mantle cell lymphomaObjective Rituximab (RTX),a chimeric anti-CD20 antibody,is associated withdirect 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.Ourstudy attempted to elucidate the mechanism of LEN-enhanced RTX-mediated killingof MCL cells.Methods Three human MCL cell lines:SP53,MINO,Grant519;freshly isolated primary MCL cells from three relaped or refractory MCL patients;and normalperipheral blood mononuclear cells (PBMCs) from healthy donors were treated withLEN and RTX,either alone or in combination.Cell proliferation,apoptosis andRTX-induced ADCC were examined to analyse the in vitro cytotoxicity of LEN plusRTX against MCL.Western blot analysis was used to investigate the signal pathwayby which different drug induced apoptosis in MCL cells.Meanwhile,we attempted toelucidate the molecular mechanism by which LEN enhanced RTX-dependent NKcell-mediated cytotoxicity.In addition,MCL-bearing xenograft models using withSCID mice were established to evaluate the in vivo anti-MCL capacity of the LENand RTX combination.Results The results showed that LEN and RTX induced growth inhibition andapoptosis of both cultured and fresh primary MCL cells.LEN enhanced RTX-inducedapoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK),Bcl-2;increasing release of cytochrome-c;enhancing activation of caspase-3,-8,-9and cleavage of PARP.Meanwhile,LEN activated NK cells and increased CD16expression on CD56^lowCD16⁺ NK cells.Whole PBMCs but not NK cell-depletedPBMCs treated with 1 1μM of LEN augmented 30% of RTX-dependent cytotoxicity.Daily treatment with LEN increased NK cells by 10 folds in SCID mice.Moreover,the combination of LEN and RTX decreased tumor burden and prolonged survival ofMCL-bearing SCID mice.Conclusions LEN plus RTX provides a synergistically therapeutic effect on MCLcells by enhancement of apoptosis and RTX-dependent NK cell-mediated cytotoxicityand may be an optimal combination in clinical trial of relapsed or refractory MCL.