Metabolic targeting of HIF-1α potentiates the therapeutic efficacy of oxaliplatin in colorectal cancer

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Abstract

Drug resistance is a major problem limiting the efficacy of chemotherapy in cancer treatment, and the hypoxia-induced stabilization of HIF-1α plays a role in this process. HIF-1α overexpression has been observed in a variety of human cancers, including colorectal cancer (CRC). Therefore, targeting HIF-1α is a promising strategy for overcoming chemoresistance to enhance the efficacy of chemotherapies in CRC. Here, we show that DNMT inhibitors can induce HIF-1α degradation to overcome oxaliplatin resistance and enhance anti-CRC therapy. We found that a low-toxicity DNMT inhibitor, zebularine, could downregulate HIF-1α expression and overcome hypoxia-induced oxaliplatin resistance in HCT116 cells and showed efficacy in HCT116 xenograft models and AOM/DSS-induced CRC mouse models. Zebularine could induce the degradation of HIF-1α protein through hydroxylation. LC-MS analysis showed a decrease in succinate in various CRC cells under hypoxia and in colon tissues of AOM/DSS-induced CRC mice. The decrease was reversed by zebularine. Tumor angiogenesis was also reduced by zebularine. Furthermore, zebularine potentiated the anticancer effect of oxaliplatin in AOM/DSS-induced CRC models. This finding provides a new strategy in which an increase in HIF-1α hydroxylation could overcome oxaliplatin resistance to enhance anti-CRC therapy.

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Grant support

This work was supported by a research grant from the National Science Council of Taiwan and the Institute of Biomedical Sciences, Academia Sinica (IBMS-CRC103-P02).

Author information

Study concept and design: C-CC. Acquisition of data: T-TW, Y-TL, S-PT, C-KL, C-TT. Analysis and interpretation of data: T-TW, S-PT, C-KLuo, C-TT, C-TS. Drafting of the manuscript: T-TW, Y-TL, C-CC. Critical revision of the manuscript for important intellectual content: C-CC. Statistical analysis: T-TW, Y-TL, S-PT. Obtained funding: C-CC. Technical or material support: C-CC. Study supervision: C-CC.

Correspondence to Ching-Chow Chen.

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