Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy

Abstract

Chloroquine (CQ) is a 4-aminoquinoline drug used for the treatment of diverse diseases. It inhibits lysosomal acidification and therefore prevents autophagy by blocking autophagosome fusion and degradation. In cancer treatment, CQ is often used in combination with chemotherapeutic drugs and radiation because it has been shown to enhance the efficacy of tumor cell killing. Since CQ and its derivatives are the only inhibitors of autophagy that are available for use in the clinic, multiple ongoing clinical trials are currently using CQ or hydroxychloroquine (HCQ) for this purpose, either alone, or in combination with other anticancer drugs. Here we show that in the mouse breast cancer cell lines, 67NR and 4T1, autophagy is induced by the DNA damaging agent cisplatin or by drugs that selectively target autophagy regulation, the PtdIns3K inhibitor LY294002, and the mTOR inhibitor rapamycin. In combination with these drugs, CQ sensitized to these treatments, though this effect was more evident with LY294002 and rapamycin treatment. Surprisingly, however, in these experiments CQ sensitization occurred independent of autophagy inhibition, since sensitization was not mimicked by Atg12, Beclin 1 knockdown or bafilomycin treatment, and occurred even in the absence of Atg12. We therefore propose that although CQ might be helpful in combination with cancer therapeutic drugs, its sensitizing effects can occur independently of autophagy inhibition. Consequently, this possibility should be considered in the ongoing clinical trials where CQ or HCQ are used in the treatment of cancer, and caution is warranted when CQ treatment is used in cytotoxic assays in autophagy research.

Cytoprotective and nonprotective autophagy in cancer therapy

“…More specifically, we have observed induction by radiation of a form of autophagy whose inhibition neither sensitizes nor protects the tumor cell from radiation. Dr. Thorburn's laboratory has also observed this nonprotective form of autophagy in response to cisplatin, 8 whereas we also have preliminary evidence for nonprotective autophagy in response to doxorubicin. 9 In this context, Lee et al recently reported that knockdown of SLC16A7/ MCT2 [solute carrier family 16, member 7 (monocarboxylic acid transporter 2)] in two primary forms of autophagy have been identified in the field of cancer therapy based on their apparent functions in the tumor cell; these are the cytoprotective form that could, in theory, be inhibited for the purpose of sensitization to radiation and chemotherapeutic drugs and the "cytotoxic" form that either mediates or contributes to the actions of these treatment modalities.…”

Autophagy in colorectal cancer: An important switch from physiology to pathology

“…Recent data indicate that only tumors that utilize excessive levels of autophagy, even in nutrientrich con ditions and in the absence of stressful stimuli, respond to autophagy inhibitors in vivo [117] . This suggests that only a fraction of cancer patients may benefit from the administration of autophagy inhibitors.…”

Chloroquine potentiates the anti-cancer effect of lidamycin on non-small cell lung cancer cells in vitro

“…Chloroquine diphosphate (CQ), an anti-malarial drug, shows potential anti-cancer effects, such as the inhibition of cell growth in human lung cancer A549 cells, human breast cancer cells, and glioma cells [8][9][10] . In addition, CQ therapy enhances the inhibitory effects of other chemotherapeutic agents on tumors.…”