title: 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.
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan 250014, China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Li
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: The Hepatosplenic Surgery Center, 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: The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Dali
authors.initials: D
authors.lastname: Zhao
authors.affiliation: The Hepatosplenic Surgery Center, 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, Qianfoshan Hospital, Shandong University, Jinan 250014, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: The Hepatosplenic Surgery Center, 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: Department of Urologic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Shaobin
authors.initials: S
authors.lastname: Ni
authors.affiliation: 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.
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
mesh_terms: D000077584:2-Methoxyestradiol; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000077584:2-Methoxyestradiol; D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D004958:Estradiol; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C530104:CCND1 protein, human; C497442:HIF1A protein, human; C467484:VEGFA protein, human
keywords: 2-Methoxyestradiol; Hepatocellular carcinoma; Hypoxia-inducible factors; Sorafenib