(2e-4e-6e-10e)-3-7-11-15-tetramethyl-2-4-6-10-14-hexadecapentaenoic-acid and Hepatitis-C

The current curative treatment modalities for hepatocellular carcinoma (HCC) are unfortunately fraught with high rates of HCC recurrence. Hence there is a need to prevent or reduce HCC recurrence after initial curative therapy. Peretinoin is a synthetic oral retinoid showing significant reduction in the incidence of recurrent or new HCC in patients who had received curative HCC therapy. Areas covered: Peretinoin is analysed against the background of molecular pathogenesis of the different causes of HCC. Publications related to peretinoin since 1996 are reviewed, covering clinical characteristics, safety and tolerance profile as well as the current status of clinical development. Expert commentary: Early phase studies are promising but we need to await the results of the ongoing phase III study of peretinoin in hepatitis C related HCC. Long term impact of peretinoin may be diminished by the foreseeable near eradication of hepatitis C by the direct acting antivirals.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Clinical Trials as Topic; Hepatitis C; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Retinoids; Risk Factors; Treatment Outcome

Hepatocellular carcinoma (HCC) develops frequently in the liver of patients with chronic hepatitis and cirrhosis caused by persistent infection with hepatitis B virus or hepatitis C virus in Asia. Several studies including ours have revealed that the risk of HCC increases in parallel with the progression of hepatic fibrosis associated with chronic hepatitis and liver cirrhosis. It may be delineated reasonably, therefore, that suppression of fibrosis by chemical (or biological) agents would be able to decrease the risk of HCC. We have demonstrated that antifibrotic agents, such as HOE 077, TJ-9 and interferon, can reduce the risk of HCC. Accordingly, antifibrotic agents are promising candidates for chemoprevention of HCC. The results of our study are discussed within the scope of the current state of the art as regards chemopreventing HCC.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Carcinoma, Hepatocellular; Chemoprevention; Drugs, Chinese Herbal; Forecasting; Hepatitis B; Hepatitis C; Humans; Interferons; Liver Cirrhosis, Experimental; Liver Neoplasms; Pyridines; Tretinoin

Sphingosine-1-phospate is a potent bioactive lipid metabolite that regulates cancer progression. Because sphingosine kinase 1 and sphingosine kinase 2 (SPHK 1/2) are both essential for sphingosine-1-phospate production, they could be a therapeutic target in various cancers. Peretinoin, an acyclic retinoid, inhibits post-therapeutic recurrence of hepatocellular carcinoma via unclear mechanisms. In this study, we assessed effects of peretinoin on SPHK expression and liver cancer development in vitro and in vivo. We examined effects of peretinoin on expression, enzymatic and promoter activity of SPHK1 in a human hepatoma cell line, Huh-7. We also investigated effects of SPHK1 on hepatocarcinogenesis induced by diethylnitrosamine using SPHK1 knockout mice. Peretinoin treatment of Huh-7 cells reduced mRNA levels, protein expression and enzymatic activity of SPHK1. Peretinoin reduced SPHK1 promoter activity; this effect of peretinoin was blocked by overexpression of Sp1, a transcription factor. Deletion of all Sp1 binding sites within the SPHK1 promoter region abolished SPHK1 promoter activity, suggesting that peretinoin reduced mRNA levels of SPHK1 via Sp1. Additionally, diethylnitrosamine-induced hepatoma was fewer and less frequent in SPHK1 knockout compared to wild-type mice. Our data showed crucial roles of SPHK1 in hepatocarcinogenesis and suggests that peretinoin prevents hepatocarcinogenesis by suppressing mRNA levels of SPHK1.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Diethylnitrosamine; Gene Expression Regulation, Enzymologic; Hepatitis C; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Neoplasms, Experimental; Mice, Knockout; Mice, Transgenic; Phosphotransferases (Alcohol Group Acceptor); Retinoids; Sphingolipids

This study examined the effects of peretinoin, an acyclic retinoid, on the survival of patients with hepatitis C virus-related hepatocellular carcinoma (HCC) who had completed curative therapy and participated in a randomized, placebo-controlled trial.. This study was an investigator-initiated retrospective cohort study. Subjects were all patients who were administered the investigational drug (peretinoin 600 mg/day, peretinoin 300 mg/day, or placebo) in the randomized trial. Survivals between the groups were compared using the log-rank test, and hazard ratios were estimated by Cox regression.. Survey data were collected from all patients (n = 392) who participated in the randomized trial, all of whom were then divided into the peretinoin 600 mg/day (n = 132), peretinoin 300 mg/day (n = 131), and placebo (n = 129) groups. At the median follow-up of 4.9 years, 5-year cumulative survival rates for patients in the 600 mg/day, 300 mg/day, and placebo groups were 73.9, 56.8, and 64.3 %, respectively. Comparison of overall survival among patients classified as Child-Pugh A revealed that survival of the 600 mg/day group (n = 105) was significantly longer than that of the placebo group (n = 108) (hazard ratio 0.575, 95 % CI 0.341-0.967; P = 0.0347).. Administration of 600 mg/day peretinoin to patients with hepatitis C virus-related HCC who have completed curative therapy may improve survival for those classified as Child-Pugh A, for whom liver function is relatively stable.

Topics: Aged; Anticarcinogenic Agents; Carcinoma, Hepatocellular; Cohort Studies; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hepatitis C; Humans; Liver Neoplasms; Male; Proportional Hazards Models; Randomized Controlled Trials as Topic; Retinoids; Retrospective Studies; Survival Rate

Clinical studies suggest that the oral acyclic retinoid Peretinoin may reduce the recurrence of hepatocellular carcinoma (HCC) following surgical ablation of primary tumours. Since hepatitis C virus (HCV) infection is a major cause of HCC, we assessed whether Peretinoin and other retinoids have any effect on HCV infection. For this purpose, we measured the effects of several retinoids on the replication of genotype 1a, 1b, and 2a HCV in vitro. Peretinoin inhibited RNA replication for all genotypes and showed the strongest antiviral effect among the retinoids tested. Furthermore, it reduced infectious virus release by 80-90% without affecting virus assembly. These effects could be due to reduced signalling from lipid droplets, triglyceride abundance, and the expression of mature sterol regulatory element-binding protein 1c and fatty acid synthase. These negative effects of Peretinoin on HCV infection may be beneficial in addition to its potential for HCC chemoprevention in HCV-infected patients.

Topics: Anticarcinogenic Agents; Antiviral Agents; Carcinoma, Hepatocellular; Hepacivirus; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Lipid Metabolism; Liver Neoplasms; Neoplasm Recurrence, Local; Peptide Chain Elongation, Translational; Recombinant Proteins; Retinoids; RNA, Viral; STAT1 Transcription Factor; Sterol Regulatory Element Binding Protein 1; Virus Assembly; Virus Release; Virus Replication

Topics: Hepatitis C; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Induced Pluripotent Stem Cells; Interferon-alpha; Quinolines; Replicon; Tretinoin; Virus Replication