Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies and it is the fourth cause of cancer-related mortality. The treatment of HCC with traditional chemotherapeutic agents such as doxorubicin has been limited due to poor efficacy, acquired resistance of the tumors and systemic toxicity. Verapamil as a P-gp inhibitor has demonstrated anti-cancer activities both in vitro and in vivo. Natural products and plant-derived compounds, such as ginger extract, have been investigated as safe and effective anti-cancer agents. Combination therapy offers preferable prognosis with less side effects. For example, the combination of chemotherapeutics with verapamil or ginger extract has been shown to exert beneficial therapeutic effects, overcome multidrug resistance and reduce side effects through modulation of different signaling pathways in tumor cells. Nano-sized formulations are designed to increase accumulation of drugs at the tumor environment and to improve solubility/bioavailability, promote retention, specificity, efficacy and safety. This review summarizes how to overcome cardiotoxicity and multidrug resistance evolved by doxorubicin in HCC treatment.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and it is the fourth cause of cancer-related mortality
Epidemiology of HCC More than 80% of HCC cases are in countries with limited medical and social care resources, especially in Eastern Asia and sub-Saharan Africa
The incidence of HCC varies according to exposure to environmental and infectious risk factors, availability of healthcare
Summary
Stimulatory effect of androgen and the protective effect of estrogen induce higher incidence of HCC in males than females (Tian et al 2015). Cirrhosis is one of the primary risk factors for developing HCC. It develops after long periods of chronic liver disease where liver cells are destroyed and fibrous tissues are formed. Lipid accumulation in obesity increases interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression and creates a status of oxidative stress, which can induce DNA damage and genomic instability (Chitapanarux and Phornphutkul 2015). Aflatoxin induces HCC through proto-oncogen activation and tumor suppressor gene p53 inactivation, DNA synthesis interruption, various chromosomal aberrations, and chromosomal strand breaks in human cells (Maurya and Trigun 2016). Initiating agents cause DNA damage, activate proto-oncogenes (Ras) and inactivate tumor suppressor genes (p53) (Lehmann et al 2016). A promoter is a compound that can promote tumor growth when subsequently applied to an initiating factor (Lehmann et al 2016)
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