Abstract
The poor prognosis of hepatocellular carcinoma (HCC) has been attributed to a high frequency of tumor metastasis and recurrence even after successful surgical resection. With less than 30% of patients benefiting from curative treatment, alternative treatment regimens for patients with advanced HCC are needed. Propyl gallate (PG), a synthetic antioxidant used in preserving food and medicinal preparations, has been shown to induce cancer cell death, but the anticancer effects of PG in HCC are unclear. In the present study, we demonstrated that PG inhibited HCC cell proliferation in vitro and in zebrafish models in vivo in a dose- and time-dependent manner. PG also induced cell apoptosis and increased the number of necrotic cells in a time- and dose-dependent manner as determined using a high-content analysis system. We found that PG also increased the intracellular levels of superoxide and reactive oxidative stress as well as the formation of autophagosomes and lysosomes. Regarding the molecular mechanism, PG did not alter the levels of autophagy-related 5 (ATG5), ATG5/12 or Beclin-1 but increased the rate of the LC3-I to LC3-II conversion, suggesting autophagy induction. PG exposure increased the levels of the pro-apoptotic proteins cleaved caspase-3, cleaved PARP, Bax, and Bad and a decreased level of the anti-apoptotic protein Bcl-2. In conclusion, we demonstrate that PG inhibits HCC cell proliferation through enhanced ROS production and autophagy activation. Finally, PG-treated cells induced cell apoptosis and may be a new candidate for HCC therapy.
Highlights
Hepatocellular carcinoma (HCC) is the malignant cancer derived from hepatocytes and is the most common cancer worldwide [1]
We examined the anticancer effects of Propyl gallate (PG) in HCC cells
We observed that PG induced a dose-dependent inhibition of the proliferation of HCC cell lines and that reactive oxygen species (ROS)-mediated apoptosis and autophagy contributes to PG-induced cell death in HCC cells
Summary
Hepatocellular carcinoma (HCC) is the malignant cancer derived from hepatocytes and is the most common cancer worldwide [1]. HCC-related mortality ranks third with regard to cancerrelated deaths worldwide but ranks second for this statistic in China [2]. PG inhibits liver cancer growth through the induction of ROS and the activation of autophagy curative treatments, including surgical resection and liver transplantation, less than one third of newly diagnosed patients are candidates for these treatments [3, 4]. An alternative treatment for patients with advanced HCC who cannot receive curative treatments, such as surgery, transplantation, transarterial chemoembolization (TACE) or radiofrequency ablation[5], is the multitargeted kinase inhibitor called sorafenib, a drug approved by the Food and Drug Administration (FDA) for advanced HCC. Developing new agents to treat HCC is challenging for researchers [8]
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