Targ Oncol DOI 10.1007/s11523-016-0452-7
REVIEW ARTICLE
Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma Supritha G. Swamy 1 & Vivek H. Kameshwar 1 & Priya B. Shubha 2 & Chung Yeng Looi 3 & Muthu K. Shanmugam 4 & Frank Arfuso 5 & Arunasalam Dharmarajan 5 & Gautam Sethi 4,5 & Nanjunda Swamy Shivananju 1 & Anupam Bishayee 6
# Springer International Publishing Switzerland 2016
Abstract Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer diagnosed worldwide. HCC occurs due to chronic liver disease and is often diagnosed at advanced stages. Chemotherapeutic agents such as doxorubicin are currently used as first-line agents for HCC therapy, but these are non-selective cytotoxic molecules with significant side effects. Sorafenib, a multi-targeted tyrosine kinase inhibitor, is the only approved targeted drug for HCC patients. However, due to adverse side effects and limited efficacy, there is a need for the identification of novel pharmacological drugs beyond sorafenib. Several agents that target and inhibit various signaling pathways involved in HCC are currently being assessed for HCC treatment. In the present review article, we summarize the diverse signal transduction
* Nanjunda Swamy Shivananju
[email protected] * Anupam Bishayee
[email protected];
[email protected] 1
Department of Biotechnology, JSS Science and Technology University, JSS Technical Institutions Campus, Mysore, Karnataka 570006, India
2
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, Karnataka, India
3
Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
4
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
5
School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Bentley, Western Australia 6009, Australia
6
Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, 18301 N. Miami Avenue, Miami, FL 33169, USA
pathways responsible for initiation as well as progression of HCC and also the potential anticancer effects of selected targeted therapies that can be employed for HCC therapy.
Key Points Hepatocellular carcinoma (HCC) is one the most common forms of liver cancer There is a need for identification of novel pharmacological drugs Several oncogenic signal transduction pathways, such as MAPK, PI3K/AKT/mTOR, Wnt/β-catenin, JAK/STAT, cMET and IGF, play critical roles in both initiation and progression of HCC. Targeted abrogation of these signaling cascades using small molecule pharmacologicals may form the basis of novel therapies for HCC patients.
1 Introduction Cancers originate due to a plethora of mutations or epimutations within the genome [1, 2]. The first approach is to identify the genes that are altered in a tumor cell. These genes are called oncogenes, which are usually either overexpressed or mutated, leading to the oncogenic phenotype. Tumor-suppressor genes are also identified, and these function as brakes in the cell cycle when required to repair the damaged DNA, and when these genes lose their functions, the cells acquire mutations due to uncontrolled cell division [1, 2]. On identification of these oncogenic genes, it is
Targ Oncol
necessary to characterize the function of various proteins encoded by them. By understanding the possible molecular mechanism(s) through which these proteins induce tumors, it is possible to develop novel therapeutic agents that can exclusively inhibit the function of these oncogenes and abrogate tumor growth [3]. Therefore, oncogenic molecules/ signaling cascades are potential targets for anticancer drug discovery, as the inhibition or activation of their function can finally lead to the elimination of tumor cells. The liver is one of the most important organs in the body and is vital for metabolic and clearance functions involving the uptake of nutrients and pathogens from the bloodstream. Some important biological actions of the liver include the breakdown and storage of the nutrients absorbed from the intestine, which is required for the normal functioning of the body. It secretes bile into the intestine to facilitate nutrient absorption [4]. The liver consists of cells called hepatocytes, which also line the bile duct [5]. Liver cancer is the second leading cause of mortality in developing countries and the sixth leading cause of cancer death among men in developed nations [6]. In developing countries, incidence rates are twoto threefold higher as compared to developed countries. Hepatocellular carcinoma (HCC) develops when there are oncogenic mutations within the genome that lead to a significantly higher rate of replication of the cells and results in abnormal cellular growth. In particular, chronic infections with hepatitis B and C virus can accelerate the development of HCC by repeatedly causing the body’s own immune system to attack the liver cells infected by the viruses [7–10]. The major risk factors for the development of HCC include liver cirrhosis, hepatitis, chronic infections with hepatitis B (HBV) or C (HCV) viruses, and environmental factors such as aflatoxin exposure and alcohol or tobacco consumption [11]. Liver cirrhosis causes functional abnormalities such as lower serum albumin level (
