Neutron radiation enhances cisplatin cytotoxicity independently of apoptosis in human head and neck carcinoma cells.
Neutron radiation enhances cisplatin cytotoxicity independently of apoptosis in human head and neck carcinoma cells.
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发表时间：
2000-10
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通讯作者：
H. Kim;M. A. Krug;I. Han;J. Ensley;G. Yoo;J. Forman;H. Kim
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作者：
H. Kim;M. A. Krug;I. Han;J. Ensley;G. Yoo;J. Forman;H. Kim
局部晚期头颈癌联合治疗的最新进展改善了局部和区域疾病控制和生存率，并具有更好的功能预后。然而，对于以顺铂为基础的新辅助化疗反应不佳的肿瘤，放射治疗后局部和局部失败率仍然很高。这一临床观察提示顺铂和光子照射耐药的共同生物学机制。在本报告中，我们研究了头颈部鳞癌（HNSCC）细胞中顺铂耐药的分子基础，并询问快中子辐射是否会增强顺铂耐药细胞中的顺铂细胞毒性。我们发现顺铂敏感性与caspase诱导相关，caspase是一种已知启动凋亡细胞死亡途径的半胱氨酸蛋白酶家族，这表明凋亡可能是顺铂细胞毒性的关键决定因素。中子辐射可有效增强顺铂在包括顺铂耐药细胞在内的HNSCCs中的细胞毒性，而光子辐射对顺铂的细胞毒性影响甚微。有趣的是，通过caspase活性测定、膜联蛋白V染色和流式细胞术分析，中子增强的顺铂细胞毒性与细胞凋亡和细胞周期调节无关。综上所述，本研究提供了顺铂耐药的分子洞察，也可能为局部晚期头颈癌患者的多模式治疗方案提供更有效的基础，包括中子辐射。
Recent advances in combined modality treatment of locally advanced head and neck cancer have improved local and regional disease control and survival with better functional outcome. However, the local and regional failure rate after radiation therapy is still high for tumors that respond poorly to cisplatin-based neoadjuvant chemotherapy. This clinical observation suggests a common biological mechanism for resistance to cisplatin and photon irradiation. In this report, we investigated the molecular basis underlying cisplatin resistance in head and neck squamous carcinoma (HNSCC) cells and asked if fast neutron radiation enhances cisplatin cytotoxicity in cisplatin-resistant cells. We found that cisplatin sensitivity correlates with caspase induction, a cysteine proteinase family known to initiate the apoptotic cell death pathway, suggesting that apoptosis may be a critical determinant for cisplatin cytotoxicity. Neutron radiation effectively enhanced cisplatin cytotoxicity in HNSCCs including cisplatin-resistant cells, whereas photon radiation had little effect on cisplatin cytotoxicity. Interestingly, neutron-enhanced cisplatin cytotoxicity was associated neither with apoptosis nor with cell cycle regulation, as determined by caspase activity assay, annexin V staining, and flow cytometric analysis. Taken together, the present study provides a molecular insight into cisplatin resistance and may also provide a basis for more effective multimodality protocols involving neutron radiation for patients with locally advanced head and neck cancer.