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

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

CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY

NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS

Año: 2022 vol. 100 p. 453 - 463

0008-4212

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-a) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (d-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of d-tocotrienol with IFN-a 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 d-tocotrienol and IFN-a 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. d-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 d-tocotrienol with IFN-a 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.