두경부 암세포에서 Metoclopramide와 Platinum 기반 항암제의 병용 처리에 의한 세포 사멸 증진 효과
Effect of Combined Treatment of Metoclopramide With Platinum-Based Drugs on Apoptosis in AMC-HN4 Cells
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Background and Objectives Metoclopramide is an antagonist of dopamine D2 receptor and is capable of alleviating chemotherapy-induced nausea and vomiting. However, its under- lying mechanisms and function in improving the efficiency of chemotherapy are not fully un- derstood. In this study, we investigated the sensitizing effect of metoclopramide on the plati- num-based drugs-mediated apoptosis in human head and neck cancer cells. Subjects and Method Apoptosis was analyzed using a cell-based cytometer. The protein ex- pression and messenger ribonucleic acid (mRNA) levels were assessed by Western blotting and real-time polymerase chain reaction, respectively. Results Metoclopramide sensitized the platinum-based drug (cisplatin and oxaliplatin)-me- diated apoptosis in AMC-HN4 cells, but not in normal cells. Mechanistically, we found that metoclopramide decreased Mcl-1 protein expression through post-translational regulation. Moreover, the overexpression of Mcl-1 prevented apoptosis by combined treatment of meto- clopramide and platinum-based drugs. Conclusion Metoclopramide induced proteasome-mediated Mcl-1 downregulation, resulting in increased sensitivity to platinum-based drugs.
Abstract
Background and Objectives Metoclopramide is an antagonist of dopamine D2 receptor and is capable of alleviating chemotherapy-induced nausea and vomiting. However, its under- lying mechanisms and function in improving the efficiency of chemotherapy are not fully un- derstood. In this study, we investigated the sensitizing effect of metoclopramide on the plati- num-based drugs-mediated apoptosis in human head and neck cancer cells. Subjects and Method Apoptosis was analyzed using a cell-based cytometer. The protein ex- pression and messenger ribonucleic acid (mRNA) levels were assessed by Western blotting and real-time polymerase chain reaction, respectively. Results Metoclopramide sensitized the platinum-based drug (cisplatin and oxaliplatin)-me- diated apoptosis in AMC-HN4 cells, but not in normal cells. Mechanistically, we found that metoclopramide decreased Mcl-1 protein expression through post-translational regulation. Moreover, the overexpression of Mcl-1 prevented apoptosis by combined treatment of meto- clopramide and platinum-based drugs. Conclusion Metoclopramide induced proteasome-mediated Mcl-1 downregulation, resulting in increased sensitivity to platinum-based drugs.