He Weiliang, Liu Ran, Yang Shao-Hua, Yuan Fang
aDepartment of Pathophysiology, Beijing Neurosurgical Institute bCenter of Brain Tumor, Beijing Institute for Brain Disorders cBeijing Key Laboratory of Brian Tumor, Beijing Neurosurgical Institute, Beijing Tiantan Hospital dDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing eDepartment of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, China fDepartment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Anticancer Drugs. 2015 Mar;26(3):293-300. doi: 10.1097/CAD.0000000000000197.
Tamoxifen, a selective estrogen receptor modulator, is widely used in the chemotherapy of estrogen receptor-positive breast cancer. Recent studies have indicated that tamoxifen might have a potential chemotherapeutic effect on glioma. In the present study, we determined the chemotherapeutic action of tamoxifen on human glioma cell lines. Methylation of 06-methylguanine-DNA methyltransferase was identified in A172, U251, and BT325 glioma cell lines, but not in the U87 cell line. Consistently, A172, U251, and BT325 cell lines are resistant to temozolomide. Tamoxifen induced significant cytotoxic action in A172, U251, BT325, and U87 cell lines. Further, Hoechst 33342 staining and apoptosis flow cytometric analysis demonstrated that tamoxifen induced apoptosis in the BT325 cell line. Mitochondrial complex analysis indicated that tamoxifen, but not other estrogen receptor modulators, dose-dependently inhibits complex I activity. In summary, our study suggests that tamoxifen might have a chemotherapeutic effect on temozolomide-resistant glioma through its direct action on mitochondrial complex I inhibition and could provide further evidence to support future clinical trials of tamoxifen for the treatment of glioblastoma.
他莫昔芬是一种选择性雌激素受体调节剂，广泛应用于雌激素受体阳性乳腺癌的化疗。最近的研究表明，他莫昔芬可能对胶质瘤具有潜在的化疗作用。在本研究中，我们确定了他莫昔芬对人胶质瘤细胞系的化疗作用。在A172、U251和BT325胶质瘤细胞系中检测到06-甲基鸟嘌呤-DNA甲基转移酶的甲基化，但在U87细胞系中未检测到。一致地，A172、U251和BT325细胞系对替莫唑胺耐药。他莫昔芬在A172、U251、BT325和U87细胞系中诱导了显著的细胞毒性作用。此外，Hoechst 33342染色和凋亡流式细胞术分析表明，他莫昔芬在BT325细胞系中诱导了凋亡。线粒体复合物分析表明，他莫昔芬而非其他雌激素受体调节剂，剂量依赖性地抑制复合物I的活性。总之，我们的研究表明，他莫昔芬可能通过直接作用于线粒体复合物I的抑制而对替莫唑胺耐药的胶质瘤具有化疗作用，并可为未来他莫昔芬治疗胶质母细胞瘤的临床试验提供进一步的证据支持。
