Antioxidants Threaten Multikinase Inhibitor Efficacy against Liver Cancer by Blocking Mitochondrial Reactive Oxygen Species.

Blanca Cucarull,Anna Colell,Montserrat Marí,María Reig,Pablo García De Frutos,Anna Tutusaus,Tania Hernáez-Alsina,Albert Morales

doi:10.3390/antiox10091336

Abstract

Sorafenib and regorafenib, multikinase inhibitors (MKIs) used as standard chemotherapeutic agents for hepatocellular carcinoma (HCC), generate reactive oxygen species (ROS) during cancer treatment. Antioxidant supplements are becoming popular additions to our diet, particularly glutathione derivatives and mitochondrial-directed compounds. To address their possible interference during HCC chemotherapy, we analyzed the effect of common antioxidants using hepatoma cell lines and tumor spheroids. In liver cancer cell lines, sorafenib and regorafenib induced mitochondrial ROS production and potent cell death after glutathione depletion. In contrast, cabozantinib only exhibited oxidative cell death in specific HCC cell lines. After sorafenib and regorafenib administration, antioxidants such as glutathione methyl ester and the superoxide scavenger MnTBAP decreased cell death and ROS production, precluding the MKI activity against hepatoma cells. Interestingly, sorafenib-induced mitochondrial damage caused PINK/Parkin-dependent mitophagy stimulation, altered by increased ROS production. Finally, in sorafenib-treated tumor spheroids, while ROS induction reduced tumor growth, antioxidant treatments favored tumor development. In conclusion, the anti-tumor activity of specific MKIs, such as regorafenib and sorafenib, is altered by the cellular redox status, suggesting that uncontrolled antioxidant intake during HCC treatment should be avoided or only endorsed to diminish chemotherapy-induced side effects, always under medical scrutiny.

Highlights

Hepatocellular carcinoma (HCC) is often diagnosed at advanced stages with poor prognosis being the third leading cause of cancer death [1,2]
Our results suggest that mitochondrial reactive oxygen species (ROS) are critical in the anti-cancer activity of multikinase inhibitors (MKIs) frequently prescribed for HCC treatment, while antioxidant compounds may alter MKI efficacy in HCC therapy and their uncontrolled consumption should be avoided during chemotherapy treatment
Anti-Tumor Activity of Multikinase Inhibitors on Liver Cancer Cells Is Affected by Previous works have demonstrated that the main MKIs used in liver cancer, such as sorafenib and regorafenib, share mitochondrial-dependent cytotoxicity

Summary

Introduction

Hepatocellular carcinoma (HCC) is often diagnosed at advanced stages with poor prognosis being the third leading cause of cancer death [1,2]. Despite recent advances in treatment, survival after HCC detection clearly needs to be improved and frequently depends on the efficacy of multikinase inhibitors (MKIs) [2,3]. Most of the liver cancer patients have received sorafenib [4] as standard systemic therapy in first line, while regorafenib [5] and cabozantinib [6] has been prescribed for second line. Current treatments for HCC have been recently reviewed by Bruix et al [7]. HCC has a complex genetic background, lacking specific driver mutations required for cancer cell survival. Metabolic weaknesses created in cancer cells by MKIs could be considered as an interesting opportunity for treatment in order to improve

Results

Discussion

Conclusion