title: Celastrol exerts synergistic effects with PHA-665752 and inhibits tumor growth of c-Met-deficient hepatocellular carcinoma in vivo.
abstract: PHA665752 (PHA), a selective small molecule c-Met Inhibitor, potently inhibited HGF-stimulated and constitutive c-Met phosphorylation, as well as HGF and c-Met-driven phenotypes of a variety of tumor cells including hepatocellular carcinoma cells. However, these effects were impaired in c-Met-deficient cancer cells. In the present study, we investigated the potential anti-human c-Met-deficient hepatocellular carcinoma effects of Celastrol, a novel triterpene, and its combination with PHA. Human hepatocellular carcinoma cells BEL-7402 (c-Met-positive) and Huh7 (c-Met-deficient) were treated with different dose of PHA with or without equal dose of Celastrol, and cell growth, cell cycle and apoptosis were evaluated, respectively, by MTT assay, flow cytometry and Caspase3/7 activity. Nude mice bearing Huh7 xenografts were used to assess the in vivo anti-tumor activity. Our results showed that Celastrol at high concentration (>1.0 μM) induced G2/M arrest and apoptosis with the activation of Caspase3/7 in Huh7 cells whereas at low concentration (<1.0 μM) had no obvious effects. Low concentration Celastrol presented significant combined effects with PHA on Huh7 cells and Huh7 xenografts in terms of growth inhibition, migration inhibition and apoptosis induction. These results suggest that Celastrol and its combination with PHA present the therapeutic potential on c-Met-deficient hepatocellular carcinoma, and deserve further preclinical and clinical studies.
authors: Fourth Affiliated Hospital of China Medical University, Shenyang, China.
authors: Hong-Lei
authors: HL
authors: Jiang
authors: Jun-Zhe
authors: JZ
authors: Jin
authors: Dan
authors: D
authors: Wu
authors: Dong
authors: D
authors: Xu
authors: Guo-Fu
authors: GF
authors: Lin
authors: Hao
authors: H
authors: Yu
authors: Dong-Yan
authors: DY
authors: Ma
authors: Jian
authors: J
authors: Liang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D053978:Pentacyclic Triterpenes; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D000970:Antineoplastic Agents; D007211:Indoles; D053978:Pentacyclic Triterpenes; D013450:Sulfones; D014315:Triterpenes; D019859:Proto-Oncogene Proteins c-met; C050414:celastrol
references: Mol Cancer Ther. 2010 May;9(5):1077-9
references: 20442310
references: Cancer Res. 2006 May 1;66(9):4758-65
references: 16651429
references: Cancer Res. 2003 Nov 1;63(21):7345-55
references: 14612533
references: J Epidemiol. 2011;21(6):401-16
references: 22041528
references: Clin Cancer Res. 2004 Oct 1;10(19):6686-94
references: 15475459
references: Cell Physiol Biochem. 2011;28(2):175-84
references: 21865725
references: Pathol Oncol Res. 2012 Apr;18(2):357-63
references: 21866424
references: J Biol Chem. 2004 Dec 31;279(53):56053-60
references: 15509580
references: Cancer Res. 1997 Aug 1;57(15):3305-13
references: 9242465
references: Curr Drug Targets. 2011 Dec;12(14):2045-58
references: 21777195
references: Oncology. 2011;81 Suppl 1:148-51
references: 22212949
references: Growth Factors. 2011 Aug;29(4):105-18
references: 21631393
references: Biol Pharm Bull. 2011;34(11):1748-52
references: 22040890
references: Cancer Prev Res (Phila). 2012 Apr;5(4):631-43
references: 22369852
references: Hepatology. 2011 Sep 2;54(3):879-89
references: 21618573
references: Ther Adv Med Oncol. 2011 Nov;3(1 Suppl):S21-35
references: 22128285