2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

Abstract

Cabozantinib is a multi-targeted tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF) receptor (VEGFR)-2, MET (c-Met, also called hepatocyte growth factor (HGF) receptor), and other receptor tyrosine kinases. Cabozantinib has recently been approved for treating advanced medullary thyroid carcinoma (MTC), but its long-term benefit remains uncertain and dose-dependent adverse events are very common. The present study has demonstrated that 2-methoxyestradiol (2ME2), an inhibitor of hypoxia-inducible factors (HIFs) and a promising anticancer agent under investigation in clinical trials, strengthens anticancer activities of cabozantinib against MTC cells in vitro and in vivo. The activated hypoxia-inducible pathways, which are mainly regulated by HIF-1, contribute to the resistance of hypoxic MTC cells to cabozantinib. Cabozantinib upregulated HIF-1α expression at translational levels and increased the expression of the downstream factors including VEGF, lactate dehydrogenase A (LDHA), HGF, and MET. 2ME2 corrected the activated pathways by cabozantinib through downregulating HIF-1α expression and inhibiting its nuclear translocation in hypoxic MTC cells. Administration of 2ME2 enhanced the efficacy of cabozantinib in suppressing the growth of MTC cell line xenografts and patient-derived xenografts established in mice. Given that 2ME2 targets insensitive hypoxic cancer cells to cabozantinib and can inhibit the activated pathways by cabozantinib, the present results warrant further investigation of 2ME2, particularly in combination with cabozantinib, for the treatment of MTC.

Inhibiting β-catenin expression promotes efficiency of radioiodine treatment in aggressive follicular thyroid cancer cells probably through mediating NIS localization

“…Previous observations pointed out that, FTC with aggressiveness may show resistance to radiotherapy. In addition, the fact that in MTC, inhibitors of HIF like 2Me2 is responsible for promoting the efficacy of anticancer drugs such as cabozantinib, had proved reversely the role of HIF-1α in progression of tumors, increased aggressiveness and poor response to therapy (39). In the present study, we also found unsatisfactory efficiency of radioiodine treatment towards xenograft tumors generated from HIF-1α/β-catenin overexpressing FTC cells, which had exhibited metastatic propensity in vitro.…”

Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds

“…The latest reports about the mechanism of action of 2-ME2 offer further insight into the importance of its influence on HIF-1α function, supported by the observations that when 2-ME2 is combined with other conventional chemotherapeutics or radiation therapy, it can increase the anticancer activity of the concomitant agent(s) or that of the irradiation [35][36][37]. Moreover, based on its inhibitory effect on HIF-1α acute myeloid leukemia has also been identified as a possible novel therapeutic target for 2-ME2 [38].…”

CT-707, a Novel FAK Inhibitor, Synergizes with Cabozantinib to Suppress Hepatocellular Carcinoma by Blocking Cabozantinib-Induced FAK Activation

“…25). In another study, cabozantinib was found to activate hypoxia-inducible pathways, which may dampen its effects; consequently, the combination of cabozantinib plus 2ME2, a HIF-1 inhibitor, displayed a preclinical synergistic antitumor effect on hepatocellular carcinoma (26).…”