title: Bufalin Reverses Resistance to Sorafenib by Inhibiting Akt Activation in Hepatocellular Carcinoma: The Role of Endoplasmic Reticulum Stress.
abstract: Sorafenib is the standard first-line therapeutic treatment for patients with advanced hepatocellular carcinoma (HCC), but its use is hampered by the development of drug resistance. The activation of Akt by sorafenib is thought to be responsible for this resistance. Bufalin is the major active ingredient of the traditional Chinese medicine Chan su, which inhibits Akt activation; therefore, Chan su is currently used in the clinic to treat cancer. The present study aimed to investigate the ability of bufalin to reverse both inherent and acquired resistance to sorafenib. Bufalin synergized with sorafenib to inhibit tumor cell proliferation and induce apoptosis. This effect was at least partially due to the ability of bufalin to inhibit Akt activation by sorafenib. Moreover, the ability of bufalin to inactivate Akt depended on endoplasmic reticulum (ER) stress mediated by inositol-requiring enzyme 1 (IRE1). Silencing IRE1 with siRNA blocked the bufalin-induced Akt inactivation, but silencing eukaryotic initiation factor 2 (eIF2) or C/EBP-homologous protein (CHOP) did not have the same effect. Additionally, silencing Akt did not influence IRE1, CHOP or phosphorylated eIF2α expression. Two sorafenib-resistant HCC cell lines, which were established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to bufalin. Thus, Bufalin reversed acquired resistance to sorafenib by downregulating phosphorylated Akt in an ER-stress-dependent manner via the IRE1 pathway. These findings warrant further studies to examine the utility of bufalin alone or in combination with sorafenib as a first- or second-line treatment after sorafenib failure for advanced HCC.
authors.affiliation: Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.affiliation: Department of Gastroenterology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Fengli
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Haijiang
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Dali
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Taishi
authors.initials: T
authors.lastname: Fang
authors.affiliation: Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Lishan
authors.initials: L
authors.lastname: Xu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002018:Bufanolides / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib
chemical_list: D002018:Bufanolides; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; C022777:bufalin