title: 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.
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
authors.forename: Han
authors.initials: H
authors.lastname: Lin
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
authors.forename: Huaqiang
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Dong
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Qiao
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. kevsun88@hotmail.com.|Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, 1005, New Zealand. kevsun88@hotmail.com.
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. jianghc@vip.163.com.
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000077584:2-Methoxyestradiol; D021581:Active Transport, Cell Nucleus; D000328:Adult; D000813:Anilides / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D005260:Female; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011725:Pyridines / Q000737:chemistry*; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D019394:Ki-67 Antigen; D011725:Pyridines; C558660:cabozantinib; D004958:Estradiol; D000077584:2-Methoxyestradiol; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5
keywords: 2-Methoxyestradiol; Cabozantinib; Hypoxia-inducible factor; Medullary thyroid carcinoma; Signal transduction pathway