The combination of hydroxychloroquine and 2-deoxyglucose enhances apoptosis in breast cancer cells by blocking protective autophagy and sustaining endoplasmic reticulum stress

2-Deoxyglucose (2-DG) can be used in antitumour research by inhibiting glycolysis and promoting the endoplasmic reticulum stress (ERS) pathway, but its clinical application is restricted due to dose-limiting side effects and survival chance for cancer cells by protective autophagy. Therefore, our research explored whether the combination of hydroxychloroquine (HCQ), an FDA-approved autophagy inhibiting drug, and 2-DG is a promising therapeutic strategy. Here, we report that HCQ combined with 2-DG can further inhibit the viability and migration and induce apoptosis of breast tumour cells compared with other individual drugs. The combination of 2-DG and HCQ can significantly reduce transplanted tumour size and tumour cell metastasis of the lung and liver in vivo. At the cellular level, HCQ suppressed autolysosome formation and terminated the autophagy process induced by 2-DG-mediated ERS, resulting in the continuous accumulation of misfolded proteins in the endoplasmic reticulum, which generated sustained ERS through the PERK-eIF2 alpha-ATF-4-CHOP axis and triggered the transformation from a survival process to cell death. Our research reinforced the research interest of metabolic disruptors in triple-negative breast cancer and emphasized the potential of the combination of 2-DG and HCQ as an anticancerous treatment.

Automated summary

HCQ combined with 2-DG can further inhibit the viability and migration of breast tumor cells and induce apoptosis. In vivo experiments have shown that the combination of 2-DG and HCQ significantly reduces tumor size and metastasis. This study deepens the research interest in metabolic disruptors for triple-negative breast cancer and emphasizes the potential of the combination of 2-DG and HCQ as an anticancer treatment.