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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 MTT 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.CO inhibited TPT-induced autophagy,which modified the cytotoxicity of TPT.However,CO failed to modify the transfer of TPT across the cytoplasmic membrane and did not increase lysosomal permeability.This study showed that CO at non-cytotoxic concentrations potentiated the cytotoxicity of TPT by interfering with autophagy,implying that CQ has significant potential as a chemotherapeutic enhancer.