Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells

• Published in: Ai zheng Vol. 30; no. 10; pp. 690 - 700
• Main Authors: Wang, Yao, Peng, Rui-Qing, Li, Dan-Dan, Ding, Ya, Wu, Xiao-Qi, Zeng, Yi-Xin, Zhu, Xiao-Feng, Zhang, Xiao-Shi
• Format: Journal Article
• Language: English
• Published: England Department of Chemotherapy,Zhongshan People's Hospital,Zhongshan,Guangdong 528403,P.R.China%State Key Laboratory of Oncology in South China,Guangzhou,Guangdong 510060,P.R.China 01.10.2011; Department of Experimental Research,Sun Yat-sen University Cancer Center,Guangzhou,Guangdong 510060,P.R.China%State Key Laboratory of Oncology in South China,Guangzhou,Guangdong 510060,P.R.China; Biotherapy Center Guangdong 510060,P.R.China; Biotherapy Center,Guangdong 510060,P.R.China%State Key Laboratory of Oncology in South China,Guangzhou,Guangdong 510060,P.R.China; Biotherapy Center,Guangdong 510060,P.R.China; Department of Experimental Research,Sun Yat-sen University Cancer Center,Guangzhou,Guangdong 510060,P.R.China; State Key Laboratory of Oncology in South China,Guangzhou,Guangdong 510060,P.R.China; Sun Yat-sen University Cancer Center
• Subjects: A549细胞; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Autophagy - drug effects; bcl-2-Associated X Protein - metabolism; Bcl-2-Like Protein 11; Cell Line, Tumor; Cell Proliferation - drug effects; Chloroquine - pharmacology; Drug Synergism; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Membrane Proteins - metabolism; Original; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Topoisomerase I Inhibitors - pharmacology; Topotecan - pharmacology; 共聚焦显微镜; 拓扑; 氯喹; 细胞毒作用; 细胞毒性; 肺癌细胞; 自噬; autophagy; lung cancer Authors' Affiliations; chemotherapy; Chloroquine
• ISSN: 1000-467X; 1944-446X
• DOI: 10.5732/cjc.011.10056

Although the anti-malaria drug chloroquine （CQ） has been shown to enhance chemotherapy and radiation sensitivity in clinical trials, the potential mechanisms underlying this enhancement are still unclear. Here, we examined the relevant mechanisms by which the multipotent CQ enhanced the cytotoxicity of topotecan （TPT）. The lung cancer cell line A549 was treated with TPT alone or TPT combined with CQ at non-cytotoxic concentrations. Cell viability was assessed using the M-IF assay. The percentage of apoptotic cells and the presence of a side population of cells were both determined by flow cytometry. Autophagy and the expression of Bcl-2 family proteins were examined by Western blotting. The accumulation of YFP-LC3 dots and the formation of acidic vesicular organelles were examined by confocal microscopy. CQ sensitized A549 cells to TPT and enhanced TPT-induced apoptosis in a Bcl-2 family protein-independent fashion. CQ inhibited TPT-induced autophagy, which modified the cytotoxicity of TPT. However, CQ failed to modify the transfer of TPT across the cytoplasmic membrane and did not increase lysosomal permeability. This study showed that CQ at non-cytotoxic concentrations potentiated the cytotoxicity of TPT by interfering with autophagy, implying that CQ has significant potential as a chemotherapeutic enhancer.