Potentiation of the Anticancer Effects by Combining Docetaxel with Ku-0063794 against Triple-Negative Breast Cancer Cells

• Published in: Cancer research and treatment Vol. 54; no. 1; pp. 157 - 173
• Main Authors: Jeon, Ye-Won, Kim, Ok-Hee, Shin, Jin Sun, Hong, Ha Eun, Kim, Cho Hee, Kim, Say-June
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Cancer Association 01.01.2022; 대한암학회
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Docetaxel - pharmacology; Enzyme Inhibitors - pharmacology; Female; Humans; Mice; Mice, Nude; Morpholines; Original; Pyrimidines; Triple Negative Breast Neoplasms - metabolism; 의학일반; mTOR inhibitor; Epithelial-mesenchymal transition; Triple-negative breast neoplasms; Autophagy; Ku-0063794; Docetaxel
• ISSN: 1598-2998; 2005-9256
• DOI: 10.4143/crt.2020.1063

mTORC1 and mTORC2 inhibition by Ku-0063794 could confer profound anticancer effects against cancer cells because it eliminates feedback activation of Akt. Herein, we aimed to determine anticancer effects of docetaxel and Ku-0063794, individually or in combination, against breast cancer cells, especially triple-negative breast cancer (TNBC) cells. MCF-7 breast cancer and MDA-MB-231 TNBC cell lines for in vitro studies and mouse xenograft model for in vivo studies were used to investigate the effect of docetaxel, Ku-0063794, or their combination. In the in vitro experiments, combination therapy synergistically reduced cell viability and induced higher apoptotic cell death in breast cancer cells than the individual monotherapies (p < 0.05). Western blot analysis and flow cytometric analysis showed that the combination therapy induced higher apoptotic cell death than the individual monotherapies (p < 0.05). In the in vivo experiment, docetaxel and Ku-0063794 combination therapy reduced the growth of MDA-MB-231 cells xenografted in the nude mice better than in the individual monotherapies (p < 0.05). Immunohistochemistry showed that the combination therapy induced the highest expression of cleaved caspase-3 and the lowest expression of Bcl-xL in the MDA-MB-231 cells xenografted in the nude mice (p < 0.05). Western blot analysis and immunofluorescence, incorporating both in vitro and in vivo experiments, consistently validated that unlike individual monotherapies, docetaxel and Ku-0063794 combination therapy significantly inhibited epithelial-mesenchymal transition (EMT) and autophagy (p < 0.05). These data suggest that docetaxel and Ku-0063794 combination therapy has higher anticancer activities over individual monotherapies against MDA-MB-231 TNBC cells through a greater inhibition of autophagy and EMT.