Induction of apoptosis in multi-drug resistant (MDR) human glioblastoma cells by SN-38, a metabolite of the camptothecin derivative CPT-11
Induction of apoptosis in multi-drug resistant (MDR) human glioblastoma cells by SN-38, a metabolite of the camptothecin derivative CPT-11
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DOI：
10.1007/s002800050592
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发表时间：
1997-03-01
影响因子：
3
通讯作者：
Barnett, GH
中科院分区：
文献类型：
--
作者：
Nakatsu, S;Kondo, S;Barnett, GH
多药耐药(MDR-1)基因及其产物P-糖蛋白(P-gp)的过度表达被认为限制了人类肿瘤的成功化疗。最近的研究表明，喜树碱(CPT)衍生物CPT-11的代谢产物SN-38对多种肿瘤具有抗肿瘤作用，但其细胞毒性机制尚不清楚。因此，我们确定了SN-38对耐多药的人胶质母细胞瘤GB-1细胞和非耐药的人胶质母细胞瘤U87-MG细胞是否具有细胞毒作用。此外，我们还确定了SN-38在这些肿瘤细胞中诱导细胞毒作用的作用。在本研究中，我们证明SN-38对GB-1和U-87 mg细胞的抗肿瘤作用明显强于CPT(分别为P<；0.01和P<；0.05)。此外，DNA片段分析、Hoechst 33258染色、原位末端标记和细胞周期分析结果表明，SN-38诱导了这些肿瘤细胞的凋亡。我们的结果表明，SN-38对恶性胶质瘤细胞具有比CPT更强的抗肿瘤作用，无论MDR表达如何，因此可以认为SN-38是一种潜在有效的新的化疗药物，可用于治疗对化疗耐药的原发或复发的恶性胶质瘤。
The overexpression of the multidrug resistance (mdr 1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumors. Recent studies demonstrate that SN-38, a metabolite of the camptothecin (CPT) derivative CPT-11, has antitumor effects on several tumors, but the mechanisms responsible for its cytotoxicity remain unclear. We therefore determined whether SN-38 has cytotoxic effects on MDR human glioblastoma GB-1 cells and non-MDR human glioblastoma U87-MG cells. Furthermore, we determined what role SN-38 plays in the induction of cytotoxicity in these tumor cells. In this study, we demonstrated that SN-38 had significantly stronger antirumor effects on GB-1 and U-87MG cells than did CPT (P < 0.01 and P < 0.05, respectively). In addition, findings obtained using a DNA fragmentation assay, Hoechst 33258 staining, in situ end-labeling and cell cycle analysis demonstrated that SN-38 induced apoptosis in these tumors. Our results suggest that SN-38 has a stronger antitumor effect on malignant glioma cells regardless of MDR expression than does CPT, and therefore can be considered a new chemotherapeutic agent potentially effective in the treatment of human primary or recurrent malignant gliomas resistant to chemotherapy.