Nelfinavir potentiation of imatinib cytotoxicity in meningioma cells via survivin inhibition.
Although most meningiomas are treated surgically, it may not be possible to completely remove atypical, malignant, and surgically inaccessible meningiomas; in the majority of these cases there is tumor recurrence. The authors have already reported initial preclinical results on the efficacy of imatinib in the treatment of meningiomas; however, a recent Phase II trial of imatinib in patients with recurrent meningiomas did not demonstrate significant antitumor activity. To enhance the activity of imatinib, the authors investigated the use of a combination therapy with nelfinavir on primary meningioma cells and meningioma cell lines IOMM-Lee and CH157. Cytotoxicity was measured using methylthiotetrazole and colony formation assays. In low-dose combination therapy with imatinib, nelfinavir potentiated the antiproliferative and anti-colony formation effects of imatinib. Primary meningioma cells responded better to combination therapy than to imatinib alone. Treatment induced a dose-dependent antiproliferative effect, decreased cell survival, and inhibited colony formation. Western blotting demonstrated decreased levels of survivin protein on combination therapy. Because meningiomas have very high levels of survivin protein, survivin inhibition by nelfinavir may represent a potential mechanism for the additive effect observed with imatinib. Moreover, an increase in the proapoptotic Bax/Bcl-2 protein ratio was demonstrated with the combination of imatinib and nelfinavir. The authors propose that nelfinavir not only potentiates imatinib efficacy, it also abrogates resistance to imatinib by decreasing survivin protein levels in meningiomas. In an in vivo assay, this combination therapy was found to be more effective than imatinib alone. More preclinical work with in vivo models is needed to determine if this new combination therapy will translate into a viable future therapy for meningiomas.
Gupta
Vinay
V
Department of Pathology, University of Southern California, Los Angeles, California, USA.
Samuleson
Christian G
CG
Su
Susan
S
Chen
Thomas C
TC
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D017320:HIV Protease Inhibitors / Q000008:administration & dosage*; D006801:Humans; D000068877:Imatinib Mesylate; D051034:Inhibitor of Apoptosis Proteins; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008579:Meningioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019888:Nelfinavir / Q000008:administration & dosage*; D009363:Neoplasm Proteins / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D001549:Benzamides; D017320:HIV Protease Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000077022:Survivin; D000068877:Imatinib Mesylate; D019888:Nelfinavir