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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\u2013Talalay 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\u2010proliferative and pro\u2010apoptotic effects in B\u2010cell 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\u2010apoptotic proteins (Bax, Bad and Bim) to anti\u2010apoptotic proteins (Bcl\u20102, Bcl\u2010xL and Mcl\u20101), triggering the cleavage of caspases \u20103, \u20109, \u20108 and PARP. Further evaluation of the combination of bortezomib with enzastaurin or lenalidomide for the treatment of B\u2010cell lymphoma is warranted, with the goal to improve the quality of life and survival of patients. Copyright \u00a9 2014 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/hon.2179","type":"journal-article","created":{"date-parts":[[2014,11,13]],"date-time":"2014-11-13T06:35:18Z","timestamp":1415860518000},"page":"166-175","source":"Crossref","is-referenced-by-count":14,"title":["The combination of bortezomib with enzastaurin or lenalidomide enhances cytotoxicity in follicular and mantle cell lymphoma cell lines"],"prefix":"10.1002","volume":"33","author":[{"given":"Maria","family":"Cosenza","sequence":"first","affiliation":[{"name":"Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic, Clinical and Public Health Medicine University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Civallero","sequence":"additional","affiliation":[{"name":"Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic, Clinical and Public Health Medicine University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Pozzi","sequence":"additional","affiliation":[{"name":"Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic, Clinical and Public Health Medicine University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"Marcheselli","sequence":"additional","affiliation":[{"name":"Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic, Clinical and Public Health Medicine University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"Bari","sequence":"additional","affiliation":[{"name":"Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic, Clinical and Public Health Medicine University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Sacchi","sequence":"additional","affiliation":[{"name":"Program of Innovative Therapies in Oncology and Haematology, Department of Diagnostic, Clinical and Public Health Medicine University of Modena and Reggio Emilia  Modena Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,11,13]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_5_2_1","DOI":"10.1053\/j.seminhematol.2010.01.003"},{"doi-asserted-by":"publisher","key":"e_1_2_5_3_1","DOI":"10.1186\/1756-8722-5-70"},{"doi-asserted-by":"publisher","key":"e_1_2_5_4_1","DOI":"10.1016\/j.clml.2011.03.029"},{"doi-asserted-by":"publisher","key":"e_1_2_5_5_1","DOI":"10.1634\/theoncologist.2011-0341"},{"doi-asserted-by":"publisher","key":"e_1_2_5_6_1","DOI":"10.3816\/CLM.2004.n.003"},{"doi-asserted-by":"publisher","key":"e_1_2_5_7_1","DOI":"10.1080\/10428190802365033"},{"doi-asserted-by":"publisher","key":"e_1_2_5_8_1","DOI":"10.1158\/1078-0432.CCR-03-0781"},{"doi-asserted-by":"publisher","key":"e_1_2_5_9_1","DOI":"10.1158\/1078-0432.CCR-06-0170"},{"doi-asserted-by":"publisher","key":"e_1_2_5_10_1","DOI":"10.1158\/1078-0432.CCR-07-0871"},{"doi-asserted-by":"publisher","key":"e_1_2_5_11_1","DOI":"10.1081\/CNV-120030218"},{"doi-asserted-by":"publisher","key":"e_1_2_5_12_1","DOI":"10.1186\/1475-2867-5-18"},{"unstructured":"National Institutes of Health (NIH).ClinicalTrials.gov2012; Available from:http:\/\/www.clinicaltrial.gov.","key":"e_1_2_5_13_1"},{"doi-asserted-by":"publisher","key":"e_1_2_5_14_1","DOI":"10.1158\/0008-5472.CAN-05-0071"},{"doi-asserted-by":"publisher","key":"e_1_2_5_15_1","DOI":"10.1182\/blood-2006-08-042747"},{"doi-asserted-by":"publisher","key":"e_1_2_5_16_1","DOI":"10.1182\/blood-2006-10-054577"},{"doi-asserted-by":"publisher","key":"e_1_2_5_17_1","DOI":"10.3109\/10428191003637290"},{"doi-asserted-by":"publisher","key":"e_1_2_5_18_1","DOI":"10.1002\/hon.974"},{"doi-asserted-by":"publisher","key":"e_1_2_5_19_1","DOI":"10.1002\/hon.875"},{"doi-asserted-by":"publisher","key":"e_1_2_5_20_1","DOI":"10.1093\/annonc\/mdm463"},{"doi-asserted-by":"publisher","key":"e_1_2_5_21_1","DOI":"10.1200\/JCO.2006.09.3146"},{"key":"e_1_2_5_22_1","first-page":"189","article-title":"Firstline treatment and maintenance in newly diagnosed multiple myeloma patients. 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