title: Small-molecule inhibition of proteasome and silencing by vascular endothelial cell growth factor-specific siRNA induce additive antitumor activity in multiple myeloma.
abstract: Angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma (MM), and MM cells secrete vascular endothelial growth factor (VEGF), which further promotes proliferation of the tumor cells. Therefore, we evaluated the anti-myeloma effect of VEGF small interfering RNA (siRNA) silencing in MM cells and whether it can be augmented by the additional application of bortezomib directed against the 26S proteasome. After transfection with VEGF siRNA, we observed a reduction of VEGF expression in all studied cell lines: OPM-2, RPMI-8226, INA-6, Jurkat, Raji, and Karpas-299, as well as in cells of MM and lymphoma patients. VEGF siRNA significantly induced apoptosis and inhibited proliferation in OPM-2 cells (P<0.0001), RPMI-8226 (P<0.0001), and INA-6 (P<0.01) versus controls. Cotreatment with VEGF siRNA and bortezomib in MM cells resulted in an exaggerated inhibition of proliferation and induction of apoptosis compared with VEGF siRNA or bortezomib alone (P<0.001). In addition, the combination of VEGF siRNA and bortezomib significantly (P<0.01) reversed multidrug resistance gene 1-dependent resistance of MM cells. Our data suggest that small-molecule inhibition of proteasome and silencing by VEGF-specific siRNA may be associated with an additive antitumor activity and might be a suitable target for new, therapeutic strategies using RNA interference in MM.
authors.affiliation: Department of Bone Marrow Transplantation, University Hospital of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. michael.koldehoff@uni-duisburg-essen.de
authors.forename: Michael
authors.initials: M
authors.lastname: Koldehoff
authors.forename: Dietrich W
authors.initials: DW
authors.lastname: Beelen
authors.forename: Ahmet H
authors.initials: AH
authors.lastname: Elmaagacli
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division; D045744:Cell Line, Tumor; D020868:Gene Silencing; D015316:Genetic Therapy; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000009:adverse effects*; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D035781:Siblings; D014162:Transfection; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D006680:HLA Antigens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D046988:Proteasome Endopeptidase Complex