Interferon-αCon1 suppresses proliferation of liver cancer cell lines in vitro and in vivo

Hisaka, Toru; Yano, Hirohisa; Ogasawara, Satoshi; Momosaki, Seiya; Nishida, Naoyo; Takemoto, Yumi; Kojiro, Sakiko; Katafuchi, Yuno; Kojiro, Masamichi

doi:10.1016/j.jhep.2004.07.012

Cited by 31 publications

(34 citation statements)

References 39 publications

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“…HAK-1B was established in the Department of Pathology at our university (26). This cell line was well characterized and has often been used for s.c. transplantation into nude mice (27). Each cell line was grown in DMEM (Sigma-Aldrich Japan, Tokyo, Japan) supplemented with 10% heat-inactivated (56C, 30 minutes) fetal Figure 1.…”

Section: Methodsmentioning

confidence: 99%

Luteolin Promotes Degradation in Signal Transducer and Activator of Transcription 3 in Human Hepatoma Cells: An Implication for the Antitumor Potential of Flavonoids

et al. 2006

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In this study, we have investigated the underlying molecular mechanism for the potent proapoptotic effect of luteolin on human hepatoma cells both in vitro and in vivo, focusing on the signal transducer and activator of transcription 3 (STAT3)/Fas signaling. A clear apoptosis was found in the luteolin-treated HLF hepatoma cells in a time-and dosagedependent manner. In concert with the caspase-8 activation by luteolin, an enhanced expression in functional Fas/CD95 was identified. Consistent with the increased Fas/CD95 expression, a drastic decrease in the Tyr 705 phosphorylation of STAT3, a known negative regulator of Fas/CD95 transcription, was found within 20 minutes in the luteolin-treated cells, leading to down-regulation in the target gene products of STAT3, such as cyclin D1, survivin, Bcl-xL, and vascular endothelial growth factor. Of interest, the rapid downregulation in STAT3 was consistent with an accelerated ubiquitin-dependent degradation in the Tyr 705 -phosphorylated STAT3, but not the Ser 727 -phosphorylated one, another regulator of STAT3 activity. The expression level of Ser 727 -phosphorylated STAT3 was gradually decreased by the luteolin treatment, followed by a fast and clear down-regulation in the active forms of CDK5, which can phosphorylate STAT3 at Ser 727 . An overexpression in STAT3 led to resistance to luteolin, suggesting that STAT3 was a critical target of luteolin. In nude mice with xenografted tumors using HAK-1B hepatoma cells, luteolin significantly inhibited the growth of the tumors in a dosage-dependent manner. These data suggested that luteolin targeted STAT3 through dual pathways-the ubiquitin-dependent degradation in Tyr 705 -phosphorylated STAT3 and the gradual down-regulation in Ser 727 -phosphorylated STAT3 through inactivation of CDK5, thereby triggering apoptosis via up-regulation in Fas/CD95.

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Section: Methodsmentioning

confidence: 99%

Luteolin Promotes Degradation in Signal Transducer and Activator of Transcription 3 in Human Hepatoma Cells: An Implication for the Antitumor Potential of Flavonoids

et al. 2006

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“…Interferon-a treatment on its own has been known to have an antitumour effect (Biron, 2001;Belardelli et al, 2002;Clemens, 2003;Hisaka et al, 2004). Indeed, a previous study has shown that IFN-a directly prevents and delays hepatocarcinogenesis by suppressing pre-neoplastic cell proliferation although this study also found that this effect may depend in part on the induction of p21 via a p53-independent pathway (Nakaji et al, 2004).…”

Section: Discussionmentioning

confidence: 56%

“…The IFN-a cytokines appear to exert their antitumour activities both indirectly by activating immune cells such as natural killer cells, macrophages, and dendritic cells (Biron, 2001;Belardelli et al, 2002), and directly by inducing apoptosis (Clemens, 2003). With regard to the latter activity, the consensus IFN-a, which is a nonnaturally occurring type I IFN with higher specific activity than the natural type I IFNs, has been shown to suppress the growth of HCC both in vitro and in vivo (Hisaka et al, 2004). Additional studies have suggested that pegylated interferon (PEG-IFN)-a, where IFN-a is joined by an amide linkage to a 40 kDa branched polyethylene glycol (PEG), may have even better antitumour effects in vivo.…”

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confidence: 99%

Combination therapy with PEG-IFN-α and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53

et al. 2007

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When the tumour suppressor p53 is activated by DNA damage, it stimulates the transcription of its target genes, which then induce cell cycle arrest or apoptosis. Here, we examined the role p53 plays in the antitumour effect of combination treatment with pegylated interferon (PEG-IFN)-a and 5-fluorouracil (5-FU), which has been shown to effectively treat advanced hepatocellular carcinoma (HCC). Nude mice were injected subcutaneously with cultured HepG2 cells, in which p53 is functional. They were treated a week later with PEG-IFN and/or 5-FU for 7 weeks, after which we measured and examined their tumours. Combination groups showed significantly lower tumour volumes and higher tumour cell apoptosis than the other groups. Combination treatment and PEG-IFN monotherapy also significantly elevated the p53 protein and mRNA levels in the tumour but only combination treatment increased the degree of p53 phosphorylation at serine46 and induced p53-regulated apoptosis-inducing protein 1 (p53AIP1) expression. The antitumour effects of combination treatment is due in part to the elevation by PEG-IFN of p53 protein and mRNA expression and in part to the DNA damage that is generated by 5-FU, which induces p53 serine46 phosphorylation, which in turn upregulates p53AIP1 expression.

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“…In Italy, Bruno et al [15] reported that the SVR to IFN-α was associated with improved outcomes in HCV-related cirrhosis. Moreover, IFN itself has an anti-tumor effect [16] , and low-dose and long-term maintenance administration of PEG-IFNα-2α decreased the incidence of HCC in non-SVR patients [17] . On the other hand, DAA has no direct anti-tumor effect, and the suppressive effect of DAA on HCC occurrence remains controversial in western countries [18][19][20][21] .…”

Section: Discussionmentioning

confidence: 99%

Efficacy and HCC development after DAA therapy for patients with chronic hepatitis C: a single center retrospective cohort study

Douhara¹,

Ogawa²,

Nakatani³

et al. 2017

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Aim:The development of hepatocellular carcinoma (HCC) is reduced after interferon based treatment in patients with chronic hepatitis C (CHC). A new therapy using direct-acting antiviral agents (DAA) has been widely applied since 2014 for CHC. The purpose of this study is to investigate the efficacy, safety and development of HCC after DAA treatment. Methods: The authors enrolled 33 consecutive patients who were treated with DAA for CHC at the hospital between January 2015 and March 2016. The laboratory data were collected at the start and 24 weeks after DAA therapy. Results: The authors analyzed 33 patients (18 male, 15 female, mean age of 68-year-old). The hepatic C virus genotypes were type 1 (27 patients) and type 2 (6 patients). The number of patients treated with sofosbuvir (SOF) + ledipasvir, daclatasvir + asunaprevir and SOF + ribavirin was 14, 13 and 6, respectively. The sustained virological response (SVR24) rate was 100%. Aspartate aminotransferase, alanine aminotransferase and FIB4-index were significantly decreased after SVR24. Adverse effects were observed in 9 patients (anemia, 5; liver function test disorder, 2; sarcoidosis, 1; pruritus, 1). With regard to HCC development, one elderly patient (3.0%) had multiple HCC recurrence after SVR24. Conclusion: DAA therapy achieved a high SVR24 rate with a good serological response. However, one patient had multiple HCC recurrence. These findings indicate that careful follow-up may be essential after DAA therapy. Key words:Chronic hepatitis C, direct-acting antiviral therapy, development of hepatocellular carcinoma, sarcoidosis ABSTRACTArticle history:

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Interferon-αCon1 suppresses proliferation of liver cancer cell lines in vitro and in vivo

Cited by 31 publications

References 39 publications

Luteolin Promotes Degradation in Signal Transducer and Activator of Transcription 3 in Human Hepatoma Cells: An Implication for the Antitumor Potential of Flavonoids

Luteolin Promotes Degradation in Signal Transducer and Activator of Transcription 3 in Human Hepatoma Cells: An Implication for the Antitumor Potential of Flavonoids

Combination therapy with PEG-IFN-α and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53

Efficacy and HCC development after DAA therapy for patients with chronic hepatitis C: a single center retrospective cohort study

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