title: Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma.
abstract: The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination. Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment.
authors.affiliation: Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.forename: Chi-Tung
authors.initials: CT
authors.lastname: Cheng
authors.forename: Shih-Chiang
authors.initials: SC
authors.lastname: Huang
authors.forename: Yeng-Yang
authors.initials: YY
authors.lastname: Chen
authors.forename: Tsung-Wen
authors.initials: TW
authors.lastname: Chen
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.forename: Yi-Yin
authors.initials: YY
authors.lastname: Jan
authors.forename: Hsi-Ming
authors.initials: HM
authors.lastname: Wang
authors.forename: Jiang-Jie
authors.initials: JJ
authors.lastname: Weng
authors.forename: Peter Mu-Hsin
authors.initials: PM
authors.lastname: Chang
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Li
authors.forename: Yee
authors.initials: Y
authors.lastname: Chao
authors.forename: Ming-Han
authors.initials: MH
authors.lastname: Chen
authors.forename: Chi-Ying F
authors.initials: CY
authors.lastname: Huang
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012118:Resorcinols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D018841:HSP90 Heat-Shock Proteins; D007093:Imidazoles; D007555:Isoxazoles; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D012118:Resorcinols; D058570:TOR Serine-Threonine Kinases; C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C546842:MTOR protein, human; C494929:PTEN protein, human; C531198:dactolisib