Anticancer Activity of Delta-Tocotrienol in Human Hepatocarcinoma: Involvement of Autophagy Induction

Simple Summary Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer (about 85-90%). In the advanced stage of the disease, existing therapies cause toxic side effects and patients often develop chemoresistance. It is therefore important to identify new compounds with low toxicity that can be used in patients with compromised liver and advanced HCC. The objective of this research was to study the antitumoral activity of delta-tocotrienol, a natural compound derived from Vitamin E, on human hepatocarcinoma cell lines. This study supports the evidence that this compound exerts an antitumoral action activating the autophagic process, leading to cancer cell death. We believe that these data may provide a basis for considering delta-tocotrienol as a potential adjuvant therapy for the treatment of advanced HCC.Abstract (1) Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Surgical resection, tumor ablation, and liver transplantation are curative treatments indicated for early-stage HCC. The management of intermediate and advanced stages of pathology is based on the use of systemic therapies which often show important side effects. Vitamin E-derivative tocotrienols (TTs) play antitumoral properties in different tumors. Here, we analyzed the activity of delta-TT (delta-TT) on HCC human cell lines. (2) We analyzed the ability of delta-TT to trigger apoptosis, to induce oxidative stress, autophagy, and mitophagy in HepG2 cell line. We evaluated the correlation between the activation of autophagy with the ability of delta-TT to induce cell death. (3) The data obtained demonstrate that delta-TT exerts an antiproliferative and proapoptotic effect in HCC cells. Furthermore, delta-TT induces the release of mitochondrial ROS and causes a structural and functional alteration of the mitochondria compatible with a fission process. Finally, delta-TT triggers selective autophagy process removing dysfunctional mitochondria. Inhibition of autophagy reversed the cytotoxic action of delta-TT. (4) Our results demonstrate that delta-TT through the activation of autophagy could represent a potential new approach in the treatment of advanced HCC.