title: In vitro and in vivo conditional sensitization of hepatocellular carcinoma cells to TNF-induced apoptosis by taxol.
abstract: High mortality among hepatocellular carcinoma (HCC) patients reflects both late diagnosis and low curability, due to pharmacoresistance. Taxol (TAX) is toxic for many human HCC-derived cell lines, yet its clinical efficacy on HCCs is poor. Combining TAX with other drugs appears a promising possibility to overcome such refractoriness. We analyzed whether combining tumor necrosis factor (TNF) with TAX would improve their toxicity. Human HCC-derived cell lines were treated with TAX or TNF, alone or combined. Apoptosis was assessed by morphology and flow-cytometry. Several pro- and anti-apoptotic molecules were evaluated by western blotting and/or enzymatic assay. After a 24 hour treatment, TNF was ineffective and TAX modestly cytotoxic, whereas HCC cells were conditionally sensitized to TNF by TAX. Indeed some relevant parameters were shifted to a prodeath setting: TNF-receptor 1 was increased, SOCS3, c-FLIP and pSTAT3 were markedly downregulated. These observations provide a significant clue to critically improve the drug susceptibility of HCC cells by combining 2 agents, TAX and TNF. The sequential application of TAX at a low dosage followed by TNF for only a short time triggered a strong apoptotic response. Of interest, prior TAX administration could also sensitize to TNF-induced apoptosis in the Yoshida AH-130 hepatoma transplanted in mice. Therefore, scrutinizing the possibility to develop similar combination drug regimens in suitable preclinical models seems highly advisable.
authors.affiliation: a Department of Clinical and Biological Sciences ; Experimental Medicine and Clinical Pathology Unit; University of Turin ; Turin , Italy.
authors.forename: V G
authors.initials: VG
authors.lastname: Minero
authors.forename: D
authors.initials: D
authors.lastname: De Stefanis
authors.forename: P
authors.initials: P
authors.lastname: Costelli
authors.forename: F M
authors.initials: FM
authors.lastname: Baccino
authors.forename: G
authors.initials: G
authors.lastname: Bonelli
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D048430:Cell Shape; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases; D017239:Paclitaxel
keywords: COL, colchicine; DAPI, 4,6-diamidino-2-phenylindole dihydrochloride; HCC, hepatocellular carcinoma; NOC, nocodazole; SOCS3; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of tanscription 3; TAX; TAX, taxol (paclitaxel); TNF; TNF, tumor necrosis factor-α; TNF-R1, TNF-receptor 1; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; apoptosis; hepatocellular carcinoma