2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and -2

Li Ma; Guangxin Li; Huaqiang Zhu; Xuesong Dong; Dali Zhao; Xian Jiang; Jie Li; Haiquan Qiao; Shaobin Ni; Xueying Sun

doi:10.1016/j.canlet.2014.09.011

2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and -2

Cancer Lett. 2014 Dec 1;355(1):96-105. doi: 10.1016/j.canlet.2014.09.011. Epub 2014 Sep 11.

Authors

Li Ma¹, Guangxin Li², Huaqiang Zhu³, Xuesong Dong⁴, Dali Zhao⁴, Xian Jiang⁴, Jie Li², Haiquan Qiao⁴, Shaobin Ni⁵, Xueying Sun⁶

Affiliations

¹ The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Department of Urologic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
² Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan 250014, China.
³ Department of General Surgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
⁴ The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
⁵ Department of Urologic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
⁶ The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: k.sun@auckland.ac.nz.

PMID: 25218350
DOI: 10.1016/j.canlet.2014.09.011

Abstract

Sorafenib is the approved systemic drug of choice for advanced hepatocellular carcinoma (HCC), but has demonstrated limited benefits because of drug resistance. 2-Methoxyestradiol (2ME2) has been shown to be a promising anticancer drug against various types of cancers and acts by dysregulating hypoxia-inducible factor (HIF)-1. Hypoxic cancer cells are extremely resistant to therapies since they elicit strong survival ability due to the cellular adaptive response to hypoxia, which is controlled by HIF-1 and HIF-2. The present study has demonstrated that sorafenib downregulated the expression of HIF-1α, making the hypoxic response switch from HIF-1α- to HIF-2α-dependent pathways, resulting in upregulation of HIF-2α, which contributes to the insensitivity of hypoxic HCC cells to sorafenib. HIF-2α played a dominant role in regulating VEGF, thus sorafenib in turn increased the expression of VEGF (a downstream molecule of both HIF-1 and HIF-2) and cyclin D1 (a downstream molecule of HIF-2), but reduced the expression of LDHA (a downstream molecule of HIF-1), in hypoxic HCC cells. 2ME2 significantly reduced the expression of both HIF-1α and HIF-2α, and their downstream molecules, VEGF, LDHA and cyclin D1, rendering hypoxic HCC cells to increased sensitivity to 2ME2. 2ME2 also inhibited the nuclear translocation of HIF-1α and HIF-2α proteins, but had no effect on their mRNA expression. 2M2 synergized with sorafenib to suppress the proliferation and induction of apoptosis of HCC cells in vitro and in vivo, and inhibited tumoral angiogenesis. These results indicate that 2ME2 given in combination with sorafenib acts synergistically for treating HCC.

Keywords: 2-Methoxyestradiol; Hepatocellular carcinoma; Hypoxia-inducible factors; Sorafenib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

2-Methoxyestradiol
Active Transport, Cell Nucleus / drug effects
Angiogenesis Inhibitors / administration & dosage
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Carcinoma, Hepatocellular / blood supply
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Proliferation / drug effects
Cyclin D1 / metabolism
Dose-Response Relationship, Drug
Drug Synergism
Estradiol / administration & dosage
Estradiol / analogs & derivatives
Hep G2 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Isoenzymes / metabolism
L-Lactate Dehydrogenase / metabolism
Lactate Dehydrogenase 5
Liver Neoplasms / blood supply
Liver Neoplasms / drug therapy*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Male
Mice, Inbred BALB C
Mice, Nude
Neovascularization, Pathologic
Niacinamide / administration & dosage
Niacinamide / analogs & derivatives
Phenylurea Compounds / administration & dosage
RNA Interference
Signal Transduction / drug effects
Sorafenib
Time Factors
Transfection
Vascular Endothelial Growth Factor A / metabolism
Xenograft Model Antitumor Assays

Substances

Angiogenesis Inhibitors
Basic Helix-Loop-Helix Transcription Factors
CCND1 protein, human
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Isoenzymes
Phenylurea Compounds
VEGFA protein, human
Vascular Endothelial Growth Factor A
Cyclin D1
endothelial PAS domain-containing protein 1
Niacinamide
Estradiol
2-Methoxyestradiol
Sorafenib
L-Lactate Dehydrogenase
Lactate Dehydrogenase 5