Review ArticleHepatocellular Carcinoma: Etiology and Current and Future Drugs
Section snippets
Etiology
Several factors associated with the etiology of HCC have a direct influence on disease progression and on the characteristic of patients.4 The greatest global HCC incidence has been reported from sub-Saharan Eastern and Western Africa, Mongolia, China, and Asia-pacific regions.5 However, the pervasiveness of HCC is lower in developed countries excluding France, Japan, and Italy. HBV, HCV, and hepatitis D virus (HDV) have a strong link with the progression of HCC; therefore, the global incidence
Regulation of kinases in HCC
Two major kinase types are dysregulated in HCC, namely the tyrosine kinases (TKs) and cyclin-dependent kinases (CDKs). These groups of kinases play a crucial role in cell growth and metabolism and are emerging targets for the treatment of HCC.
Current drugs for HCC
The development of HCC involves dysregulation of the cell cycle, apoptosis, and many other cellular pathways. Tumor cell progression involves mutations in various proteins responsible for the regulation of cell cycle.80 Hence, the recent advances in the treatment of HCC include molecules that target proteins such as CDKs or growth factors to suppress the tumor development.91
Prospects for future research
Molecular studies of HCC have determined abnormal activation of different signaling pathways, which illustrate key targets for novel molecular therapies. Other agents such as linifanib, ramucirumab, bevacizumab, axitinib, cediranib, dovitinib, vandetanib, oratinib, nintedanib etc. have demonstrated potential results in clinical phase 1-2 trials, but further studies are required to indicate their efficacy. Overall, combination therapies that would provide a synergistic effect and reduce drug
Conclusion
In conclusion, genetic alteration leads to hepatocarcinogenesis that affects multiple signaling cascades and results in uncontrolled growth of the hepatocytes. There are systemic targeted therapies that focus on the critical steps of the carcinogenic pathways but limits in the widespread systemic toxicity. Hence, drugs such as Milciclib seem to be a promising candidate for combination therapies in patients with cancer. On account of the heterogeneity of HCC, proper combinative targeted therapy
Conflicts of interest
All authors have none to declare.
References (142)
- et al.
The global epidemiology of hepatocellular carcinoma: present and future
Clin Liver Dis
(2011) - et al.
Mechanisms of HBV-related hepatocarcinogenesis
J Hepatol
(2010) - et al.
Effects of hepatitis B virus X protein on the development of liver cancer
J Lab Clin Med
(2006) Interaction of the hepatitis B virus X protein with the Crm1-dependent nuclear export pathway
J Biol Chem
(2001)Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma
Clin Microbiol Infect
(2016)- et al.
How do persistent infections with hepatitis C virus cause liver cancer?
Curr Opin Virol
(2015) - et al.
Innate and adaptive immune responses in HCV infections
J Hepatol
(2014) Hepatitis C virus-induced hepatocarcinogenesis
J Hepatol
(2009)The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide
J Hepatol
(2006)Statements from the Taormina expert meeting on occult hepatitis B virus infection
J Hepatol
(2008)
Occult hepatitis B
Lancet Infect Dis
HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS)
Lancet
Viral hepatitis and HIV co-infection
Antivir Res
Increasing burden of liver disease in patients with HIV infection
Lancet
How should we deal with patient heterogeneity in economic evaluation: a systematic review of national pharmacoeconomic guidelines
Value Health
The angiogenic switch in carcinogenesis
Semin Canc Biol
Epidemiology of viral hepatitis and hepatocellular carcinoma
Gastroenterology
Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin hepatocarcinogenesis
Mutat Res
The changing pattern of epidemiology in hepatocellular carcinoma
Dig Liver Dis
Risk of HCC: genetic heterogeneity and complex genetics
J Hepatol
Inherited hepatocellular carcinoma
Best Pract Res Clin Gastroenterol
The role of tyrosine kinase inhibitors in hepatocellular carcinoma
Clin Adv Hematol Oncol
Targeting cell cycle and apoptosis for the treatment of human malignancies
Curr Opin Cell Biol
Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature
Methods Enzymol
Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study
Eur J Cancer
Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet
Epidemiology of hepatocellular carcinoma: consider the population
J Clin Gastroenterol
Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer
Cancer
The etiology of hepatocellular carcinoma and consequences for treatment
Oncol
Viral hepatitis and hepatocellular carcinoma: etiology and management
J Gastrointest Oncol
Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis
J Carcinog
Liver fibrosis
J Clin Invest
Hepatitis B and hepatocellular carcinoma
Hepatology
Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis
J Natl Cancer Inst
The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients
Genome Res
Patterns of single- and double-stranded hepatitis B virus DNA and viral antigen accumulation in infected liver cells
J Gen Virol
Hepatitis B-associated fibrosis and fibrosis/cirrhosis regression with nucleoside and nucleotide analogs
Expert Rev Gastroenterol Hepatol
Chronic hepatitis B with advanced fibrosis or cirrhosis: impact of antiviral therapy
Rev Gastroenterol Disord
Prevalence of fibrosis and cirrhosis in chronic hepatitis B: implications for treatment and management
Am J Gastroenterol
Discussion on differential gene expression between chronic hepatitis B and C hepatic lesion
Gastroenterology
HBV induced HCC: major risk factors from genetic to molecular level
BioMed Res Int
Detection of the hepatitis B virus X protein (HBx) antigen and anti-HBx antibodies in cases of human hepatocellular carcinoma
J Clin Microbiol
Direct association and nuclear import of the hepatitis B virus X protein with the NF-kappaB inhibitor IkappaBalpha
Mol Cell Biol
Cytosol is the prime compartment of hepatitis B virus X protein where it colocalizes with the proteasome
Oncogene
Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent
Atiprimod. Mol Cancer Ther
Association between hepatitis C and hepatocellular carcinoma
J Global Infect Dis
Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?
Hepatology
Hepatitis C virus-induced hepatocellular carcinoma
Clin Mol Hepatol
Hepatitis C virus and hepatocellular carcinoma
Biology
Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma
Nat Rev Canc
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