Chemotherapy for hepatocellular carcinoma: The present and the future

Abstract

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it’s still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatin- and gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…Chemotherapy is commonly performed especially for advanced HCC, and sorafenib has been widely utilized as the standard agent . Sorafenib treatment induced apoptosis by decreasing the Bcl‐2/BAX ratio as well as ER stress followed by autophagy via activation of protein kinase R‐like endoplasmic reticulum kinase (PERK)/activating transcription factor 4 (ATF4) pathways in HepG2 cells 1.…”

“…86 Chemotherapy is commonly performed especially for advanced HCC, and sorafenib has been widely utilized as the standard agent. 87 Sorafenib treatment induced apoptosis by decreasing the Bcl-2/BAX ratio as well as ER stress followed by autophagy via activation of protein kinase R-like endoplasmic reticulum kinase (PERK)/activating transcription factor 4 (ATF4) pathways in HepG2 cells 88 1. Melatonin increased the sensitivity of HepG2 cells to sorafenib leading to enhanced cell death and inhibition of proliferation by inhibiting PERK/ATF4-mediated autophagy in vitro.…”

Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

“…Sorafenib resistance remains a major problem for the effective treatment of hepatocellular carcinoma because sorafenib is the only standard clinical treatment against the advanced form of this disease (Chen et al, 2015a). The therapeutic benefit of this compound is limited, and invariably, tumour progression reappears (Le Grazie et al, 2017). Therefore, it is necessary to identify signalling pathways that promote drug resistance and to explore potential strategies to overcome resistance to find more effective therapies.…”

Exenatide induces autophagy and prevents the cell regrowth in HepG2 cells

“…In fact, standard systemic chemotherapy is typically not effective for HCC treatment, and until now sorafenib seems to be the only available treatment for advanced stages (Le Grazie et al, 2017[15]), which makes the search for new chemotherapeutics increasingly important and necessary.…”