Enhancement radiosensitization of breast cancer cells by deguelin.
OBJECTIVE
Radiation can activate the phosphatidylinositol 3-kinase/Akt pathway and cannot downregulate survivin expression in breast cancer cells. Deguelin induces apoptosis in breast cancer cells by inhibiting pAkt and survivin expression. In this study, we assessed the effect of deguelin on radiosensitization of human breast cancer cells and its possible mechanism.


METHODS
Deguelin and radiation were administrated in MDA-MB-231 human breast cancer cells. The cytotoxic interactions and mutual influences between these 2 modalities were analyzed by a series of assays including clonogenic, flow cytometric, and Western blotting.


RESULTS
Phospho-Akt expression and survivin expression significantly decreased after 10 nM deguelin treatment, while phospho-Akt expression increased and survivin expression did not alter after radiation (3 Gy). However, phospho-Akt expression and survivin expression further significantly decreased after deguelin combined with radiation treatment. Deguelin combined with radiation markedly decreased clonogenic cell survival. After treatment of deguelin (10 nM) combined with radiation (3 Gy), caspase-dependent apoptosis was significantly increased and cell cycle was arrested in the G2-M phase in MDA-MB-231 cells.


CONCLUSIONS
Deguelin attenuates radiation-induced prosurvival Akt signaling and enhances the radiosensitivity of MDA-MB-231 cells, and the mechanisms for this action may include inhibiting phospho-Akt and survivin expression, increasing caspase-dependent apoptosis, and prolonging cell cycle arrest in the G2-M phase.
Yi
Tongbo
T
Department of Breast and Endocrine Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
Li
Haizhi
H
Wang
Xuanyi
X
Wu
Zhengyan
Z
D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077022:Survivin
C107489:BIRC5 protein, human; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D000077022:Survivin; D012402:Rotenone; D019869:Phosphatidylinositol 3-Kinases; D053148:Caspase 3; C107676:deguelin