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

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.

journal_name

Cancer Lett

journal_title

Cancer letters

authors

Ma L,Li G,Zhu H,Dong X,Zhao D,Jiang X,Li J,Qiao H,Ni S,Sun X

doi

10.1016/j.canlet.2014.09.011

subject

Has Abstract

pub_date

2014-12-01 00:00:00

pages

96-105

issue

1

eissn

0304-3835

issn

1872-7980

pii

S0304-3835(14)00510-2

journal_volume

355

pub_type

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