Faculty of Pharmacy, College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
Biochem Biophys Res Commun. 2011 Dec 9;416(1-2):222-5. doi: 10.1016/j.bbrc.2011.11.053. Epub 2011 Nov 19.
Gliomas are the most common brain tumors in adults and account for more than half of all brain tumors. Despite intensive clinical investigations, average survival for the patients harboring the malignancy has not been significantly improved. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), shown to have potent and cancer-selective killing activity, has drawn considerable attention as a promising anti-cancer therapy. In an attempt to develop TRAIL as an anti-cancer therapy for gliomas, tumor suppressor activity of TRAIL was assessed using human glioma cell lines such as U373MG, U343MG, U87MG and LN18. U343MG, U87MG and LN18 cells were susceptible to TRAIL; however, U373MG cells were completely refractory to TRAIL. Resistance to the applied therapies is a key issue in cancer treatment; thus, various combination treatments were evaluated using U373MG cells to identify a better regimen. Unlike Doxorubicin, Etoposide, Actinomycin D and Wortmannin, a proteasome inhibitor MG132 significantly enhanced TRAIL-induced apoptosis. Similarly, other proteasome inhibitors, including Lactacystin, Proteasome inhibitor I and Velcade (Bortezomib), also enhanced apoptotic activity of TRAIL. Among these proteasome inhibitors, Velcade, the only approved drug, was as effective as MG132 in enhancing TRAIL-induced apoptosis. Both Velcade and MG132 increased the protein levels of DR5, a TRAIL receptor known to be up-regulated by p53, in U373MG cells where p53 is mutated. Our data indicate that proteasome inhibitors up-regulate DR5 in a p53-independent manner and a combination therapy comprising TRAIL and Velcade become a better treatment regimen for gliomas.
神经胶质瘤是成年人最常见的脑肿瘤，占所有脑肿瘤的一半以上。尽管进行了深入的临床研究，但携带这种恶性肿瘤的患者的平均存活时间并没有得到显著改善。肿瘤坏死因子相关凋亡诱导配体（TRAIL）具有强大的、选择性杀伤癌细胞的作用，作为一种很有前途的抗癌治疗方法引起了广泛关注。为了将 TRAIL 开发为治疗神经胶质瘤的抗癌疗法，研究人员使用 U373MG、U343MG、U87MG 和 LN18 等人类神经胶质瘤细胞系评估了 TRAIL 的肿瘤抑制活性。U343MG、U87MG 和 LN18 细胞对 TRAIL 敏感；然而，U373MG 细胞对 TRAIL 完全耐药。对应用疗法的耐药性是癌症治疗中的一个关键问题；因此，使用 U373MG 细胞评估了各种联合治疗方案，以确定更好的治疗方案。与阿霉素、依托泊苷、放线菌素 D 和渥曼青霉素不同，蛋白酶体抑制剂 MG132 显著增强了 TRAIL 诱导的细胞凋亡。同样，其他蛋白酶体抑制剂，包括 Lactacystin、蛋白酶体抑制剂 I 和硼替佐米（Velcade），也增强了 TRAIL 的促凋亡活性。在这些蛋白酶体抑制剂中，唯一获得批准的药物 Velcade 与 MG132 一样有效，能够增强 TRAIL 诱导的 U373MG 细胞凋亡。Velcade 和 MG132 均增加了 U373MG 细胞中 DR5 的蛋白水平，DR5 是一种 TRAIL 受体，已知其表达水平可被 p53 上调，而 U373MG 细胞中的 p53 发生了突变。我们的数据表明，蛋白酶体抑制剂以 p53 非依赖的方式上调 DR5，TRAIL 和 Velcade 的联合治疗可能成为治疗神经胶质瘤的更好治疗方案。
