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

• Published in: Oncogene Vol. 39; no. 2; pp. 414 - 427
• Main Authors: Wei, Tzu-Tang, Lin, Yi-Ting, Tang, Shao-Pu, Luo, Cong-Kai, Tsai, Chiou-Tsun, Shun, Chia-Tung, Chen, Ching-Chow
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2020; Nature Publishing Group
• Subjects: 101/58; 13/109; 13/51; 13/95; 45/90; 631/67/1059/2326; 631/67/2328; 64/60; Angiogenesis; Animal models; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Cancer; Cancer therapies; Cell Biology; Chemoresistance; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - blood supply; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cytidine - analogs & derivatives; Cytidine - pharmacology; Down-Regulation - drug effects; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Female; Gene Expression Regulation, Neoplastic - drug effects; HCT116 Cells; Human Genetics; Humans; Hydroxylation; Hydroxylation - drug effects; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Internal Medicine; Medicine; Medicine & Public Health; Mice; Molecular Targeted Therapy; Neovascularization, Pathologic - drug therapy; Oncology; Oxaliplatin; Oxaliplatin - pharmacology; Oxaliplatin - therapeutic use; Protein Stability - drug effects; Proteolysis - drug effects; Toxicity; Vascular Endothelial Growth Factor A - metabolism; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0999-8

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.