Laurent Nathalie, de Boüard Sophie, Guillamo Jean-Sébastien, Christov Christo, Zini Roland, Jouault Hélène, Andre Patrice, Lotteau Vincent, Peschanski Marc
INSERM U421, Faculté de Médecine 2 étage, Creteil, France.
Mol Cancer Ther. 2004 Feb;3(2):129-36.
Glioblastoma is a therapeutic challenge as a highly infiltrative, proliferative, and resistant tumor. Among novel therapeutic approaches, proteasome inhibition is very promising in controlling cell cycle and inducing apoptosis. This study investigated the effect of ritonavir, a protease inhibitor of the HIV and a proteasome modulator, on glioma cells. The hypothesis was that proteasome modulation, mainly by only inhibiting proteasome chymotrypsin-like activity, could be sufficient to control tumor progression. The experiments were done on a human glioblastoma-derived GL15 cell line and a rat nitrosourea-induced gliosarcoma 9L cell line. Culturing conditions included monolayer cultures, transplantations into brain slices, and transplantations into rat striata. The study demonstrates that ritonavir, by inhibiting the chymotrypsin-like activity of the proteasome, has cytostatic and cytotoxic effects on glioma cells, and can induce resistances in vitro. Ritonavir was unable to control tumor growth in vivo, likely because the therapeutic dose was not reached in the tumor in vivo. Nevertheless, ritonavir might also be beneficial, by decreasing tumor infiltration, in the reduction of the deleterious peritumor edema in glioblastoma.
胶质母细胞瘤是一种具有高度浸润性、增殖性和耐药性的肿瘤，治疗颇具挑战性。在新型治疗方法中，蛋白酶体抑制在控制细胞周期和诱导细胞凋亡方面很有前景。本研究调查了利托那韦（一种HIV蛋白酶抑制剂和蛋白酶体调节剂）对胶质瘤细胞的影响。研究假设是，主要通过仅抑制蛋白酶体类胰凝乳蛋白酶活性来调节蛋白酶体，可能足以控制肿瘤进展。实验在源自人胶质母细胞瘤的GL15细胞系和大鼠亚硝基脲诱导的胶质肉瘤9L细胞系上进行。培养条件包括单层培养、移植到脑片中以及移植到大鼠纹状体中。该研究表明，利托那韦通过抑制蛋白酶体的类胰凝乳蛋白酶活性，对胶质瘤细胞具有细胞生长抑制和细胞毒性作用，并能在体外诱导耐药性。利托那韦在体内无法控制肿瘤生长，可能是因为在体内肿瘤中未达到治疗剂量。然而，利托那韦通过减少肿瘤浸润，在减轻胶质母细胞瘤有害的瘤周水肿方面可能也有益处。
