title: Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma.
abstract: The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world. Although sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects, currently sets the new standard for advanced HCC, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical if outcomes are to be improved. In this study we tested the hypothesis that hypoxia caused by the antiangiogenic effects of sustained sorafenib therapy could induce sorafenib resistance as a cytoprotective adaptive response, thereby limiting sorafenib efficiency. We found that HCCs, clinically resistant to sorafenib, exhibit increased intratumor hypoxia compared with HCCs before treatment or HCCs sensitive to sorafenib. Hypoxia protected HCC cells against sorafenib and hypoxia-inducible factor 1 (HIF-1α) was required for the process. HCC cells acquired increased P-gp expression, enhanced glycolytic metabolism, and increased nuclear factor kappa B (NF-κB) activity under hypoxia. EF24, a molecule having structural similarity to curcumin, could synergistically enhance the antitumor effects of sorafenib and overcome sorafenib resistance through inhibiting HIF-1α by sequestering it in cytoplasm and promoting degradation by way of up-regulating Von Hippel-Lindau tumor suppressor (VHL). Furthermore, we found that sustained sorafenib therapy led to increased intratumor hypoxia, which was associated with sorafenib sensitivity in HCC subcutaneous mice tumor models. The combination of EF24 and sorafenib showed synergistically effects against metastasis both in vivo and in vitro. Synergistic tumor growth inhibition effects were also observed in subcutaneous and orthotopic hepatic tumors.
  
  
  CONCLUSIONS
  Hypoxia induced by sustained sorafenib treatment confers sorafenib resistance to HCC through HIF-1α and NF-κB activation. EF24 overcomes sorafenib resistance through VHL-dependent HIF-1α degradation and NF-κB inactivation. EF24 in combination with sorafenib represents a promising strategy for HCC.
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Liang
authors.forename: Tongsen
authors.initials: T
authors.lastname: Zheng
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Song
authors.forename: Jiabei
authors.initials: J
authors.lastname: Wang
authors.forename: Dalong
authors.initials: D
authors.lastname: Yin
authors.forename: Luoluo
authors.initials: L
authors.lastname: Wang
authors.forename: Haitao
authors.initials: H
authors.lastname: Liu
authors.forename: Lantian
authors.initials: L
authors.lastname: Tian
authors.forename: Xiang
authors.initials: X
authors.lastname: Fang
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Meng
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Jiaren
authors.initials: J
authors.lastname: Liu
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004359:Drug Therapy, Combination; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D010881:Piperidones / Q000494:pharmacology*; D000077157:Sorafenib; D016896:Treatment Outcome; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D010671:Phenylurea Compounds; D010881:Piperidones; D009536:Niacinamide; D000077157:Sorafenib; D051794:Von Hippel-Lindau Tumor Suppressor Protein