Tumor Biology

, Volume 37, Issue 1, pp 381–391 | Cite as

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

  • Han Lin
  • Xian Jiang
  • Huaqiang Zhu
  • Wenjing Jiang
  • Xuesong Dong
  • Haiquan Qiao
  • Xueying Sun
  • Hongchi Jiang
Original Article

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.

Keywords

Cabozantinib Medullary thyroid carcinoma 2-Methoxyestradiol Hypoxia-inducible factor Signal transduction pathway 

Notes

Acknowledgments

This work was supported by grants from the National Natural Scientific Foundation (81272467, 81472321, and 81270527), the Health Industry Special Projects of Research (201202007), The Youth Scientific Fund of Heilongjiang Province (QC2013C098), and The First Affiliated Hospital of Harbin Medical University (2014B22), China. Lin H and Jiang X contributed equally to this work.

Conflicts of interest

None

Supplementary material

13277_2015_3816_MOESM1_ESM.docx (56 kb)
ESM 1 Additional detailed materials and methods. (DOCX 56 kb)
13277_2015_3816_MOESM2_ESM.docx (92 kb)
Fig. S1 Cabozantinib inhibits phosphorylation of MET, VEGFR2 and RET in MTC cells. (DOCX 91 kb)
13277_2015_3816_MOESM3_ESM.docx (224 kb)
Fig. S2 2ME2 and cabozantinib regulate tumoral gene expression examined by immunoblotting and immunohistochemistry. (DOCX 224 kb)
13277_2015_3816_MOESM4_ESM.docx (120 kb)
Fig. S3 Images of sections from patient-derived xenografts stained by hematoxylin/eosin (HE) and immunostained by an anti-calcitonin antibody. (DOCX 120 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Han Lin
    • 1
  • Xian Jiang
    • 1
  • Huaqiang Zhu
    • 2
  • Wenjing Jiang
    • 1
  • Xuesong Dong
    • 1
  • Haiquan Qiao
    • 1
  • Xueying Sun
    • 1
    • 3
  • Hongchi Jiang
    • 1
  1. 1.Key Laboratory of Hepatosplenic Surgery, Department of General SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Department of General SurgeryProvincial Hospital Affiliated to Shandong UniversityJinanChina
  3. 3.Department of Molecular Medicine & Pathology, Faculty of Medical and Health SciencesThe University of AucklandAucklandNew Zealand

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