Delta-tocotrienol enhances the anti-tumor effects of interferon alpha through reactive oxygen species and Erk/MAPK signaling pathways in hepatocellular carcinoma cells

• Published in: Canadian journal of physiology and pharmacology Vol. 100; no. 5; p. 453
• Main Authors: Lucci, Alvaro, Vera, Marina C, Comanzo, Carla G, Lorenzetti, Florencia, Ferretti, Anabela C, Ceballos, María Paula, Quiroga, Ariel D, Alvarez, María de Luján, Carrillo, María Cristina
• Format: Journal Article
• Language: English
• Published: Canada 01-05-2022
• Subjects: Apoptosis; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Humans; Interferon-alpha - pharmacology; Interferon-alpha - therapeutic use; Liver Neoplasms - pathology; Reactive Oxygen Species - metabolism; Signal Transduction; Vitamin E - analogs & derivatives; Vitamin E - pharmacology; Vitamin E - therapeutic use; interféron; Notch1; tocotriénol; apoptosis; apoptose; carcinome hépatocellulaire; interferon; p38 MAPK; hepatocellular carcinoma; tocotrienol; Erk
• ISSN: 1205-7541
• DOI: 10.1139/cjpp-2021-0606

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN-α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN-α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared with single therapies. Combining δ-tocotrienol and IFN-α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase (MMP) 7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and reactive oxygen species (ROS) generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anti-cancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN-α therapy showed promising results for HCC cell treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.