Abstract
The present study investigated the effect of YC-1, a novel anti-cancer agent, on the chemo-sensitivity of hepatocellular carcinoma (HCC). YC-1 was administered with chemo-cytotoxic drug, cisplatin, both in vitro and in vivo. YC-1 alone downregulated the expression of phosphorylated form of signal transducers and activators of transcription 3 (P-Stat3[705]), a key mediator in chemo-resistance. When combined with cisplatin, YC-1 further promoted tumor cell apoptosis, decreased the expression of P-Stat3(705), Bcl-xL, CyclinD1 and survivin, and induced the cleavage of caspase 9 and PARP. Overexpression of Stat3 reversed YC-1 induced cell death. YC-1 inhibited Stat3 activity by enhancing the polyubiquitination of P-Stat3(705) induced by cisplatin. In the in vivo setting, YC-1 combined with cisplatin remarkably suppressed tumor growth in a HCC xenograft model, and this effect was also accompanied by YC-1 mediated downregulation of P-Stat3(705), Bcl-xL, Cyclin D1 and survivin, and induction of cleaved caspase 9 and PARP in the tumor tissues. In conclusion, the present study demonstrated a novel anti-cancer effect of YC-1 in enhancing chemo-sensitivity of HCC cells to cisplatin through a Stat3 dependent manner. This finding provides insight into design of a new therapeutic strategy to improve efficacy of chemotherapy in HCC patients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Caspase 9 / biosynthesis
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Caspase 9 / genetics
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Cisplatin / pharmacology*
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Cyclin D
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Cyclins / biosynthesis
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Cyclins / genetics
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Drug Resistance, Neoplasm / drug effects
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Drug Synergism
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Indazoles / pharmacology*
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Indazoles / therapeutic use
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Inhibitor of Apoptosis Proteins
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Liver Neoplasms, Experimental / drug therapy
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Liver Neoplasms, Experimental / metabolism
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Liver Neoplasms, Experimental / pathology
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Mice
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / genetics
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases / biosynthesis
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Poly(ADP-ribose) Polymerases / genetics
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Protein Processing, Post-Translational / drug effects
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STAT3 Transcription Factor / antagonists & inhibitors*
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STAT3 Transcription Factor / metabolism
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Survivin
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Ubiquitination / drug effects
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Xenograft Model Antitumor Assays
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bcl-X Protein / biosynthesis
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bcl-X Protein / genetics
Substances
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Antineoplastic Agents
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BCL2L1 protein, human
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BIRC5 protein, human
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Cyclin D
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Cyclins
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Indazoles
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Survivin
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bcl-X Protein
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3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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CASP9 protein, human
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Caspase 9
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Cisplatin