Inhibition of telomerase increases the susceptibility of human malignant glioblastoma cells to cisplatin-induced apoptosis
Inhibition of telomerase increases the susceptibility of human malignant glioblastoma cells to cisplatin-induced apoptosis
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DOI：
10.1038/sj.onc.1201754
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发表时间：
1998-04-30
期刊：
影响因子：
8
通讯作者：
Cowell, JK
中科院分区：
文献类型：
--
作者：
Kondo, Y;Kondo, S;Cowell, JK
恶性胶质母细胞瘤生长非常迅速，通常对破坏DNA的药物或伽玛射线具有抵抗力，如果治疗能使肿瘤细胞更容易死亡，这显然代表着治疗成功的显著改善。近年来，端粒酶作为治疗癌细胞的靶点已成为肿瘤学家关注的焦点。端粒酶延长端粒DNA重复序列(TTAGGG)(N)并在保护和复制DNA方面起重要作用，确实，绝大多数肿瘤细胞都表达端粒酶活性，而正常体细胞，除了少数细胞外，不表达端粒酶活性，由于端粒酶对于保护DNA是必不可少的，我们可能能够通过抑制端粒酶活性来使肿瘤对破坏DNA的药物更敏感。在本研究中，我们使用了顺铂敏感的U87-MG细胞和顺铂耐药的U251-MG细胞，U87-MG细胞不表达端粒酶活性，而U251-MG细胞中高度检测到端粒酶活性。有趣的是，用反义端粒酶表达载体抑制端粒酶不仅降低了U251-MG细胞的端粒酶活性，而且增加了对顺铂诱导的细胞凋亡的敏感性。这些发现表明，反义端粒酶治疗可能代表着对抗癌药物耐药的肿瘤进行一种新的化疗增敏。
Malignant glioblastomas grow very rapidly and are generally resistant to either DNA-damaging drugs or gamma-irradiation, If tumor cells could be made more susceptible to cell death with treatments, this would clearly represent a significant improvement in the success of treatment. Recently, telomerase has become a focus of interest among oncologists as a target for treating cancer cells. Telomerase elongates telomeric DNA repeats (TTAGGG)(n) and is important in protecting and replicating DNA, The vast majority of tumor cells, indeed, express telomerase activity whereas normal somatic cells, except for a few cells, do not, Since telomerase is essential for protecting DNA, we may be able to make tumors more sensitive to treatments with DNA-damaging drugs by inhibiting telomerase activity, In this study, we used cis-diamminedichloroplatinum (cisplatin)-sensitive U87-MG cells and cisplatin-resistant U251-MG of human malignant glioblastoma cell lines, U87-MG cells did not express telomerase activity, whereas telomerase was highly detected in U251-MG cells. Interestingly, inhibition of telomerase with an antisense telomerase expression vector not only decreased telomerase activity but also increased susceptibility to cisplatin-induced apoptotic cell death in U251-MG cells. These findings suggest that treatment with antisense telomerase may represent a new chemosensitisation for tumors resistant to anticancer drugs.