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

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.

• Authors: Tzu-Tang Wei, Yi-Ting Lin, Shao-Pu Tang, Cong-Kai Luo, Chiou-Tsun Tsai, Chia-Tung Shun, Ching-Chow Chen
• Journal: Oncogene (Oncogene) Vol. 39 Issue 2 Pg. 414-427 (01 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 31477841 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Vascular Endothelial Growth Factor A
• Oxaliplatin
• Cytidine
• pyrimidin-2-one beta-ribofuranoside

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Colorectal Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Cytidine (analogs & derivatives, pharmacology)
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• Humans
• Hydroxylation (drug effects)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Molecular Targeted Therapy
• Neovascularization, Pathologic (drug therapy)
• Oxaliplatin (pharmacology, therapeutic use)
• Protein Stability (drug effects)
• Proteolysis (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays