Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma

Lilia Turcios, Francesc Marti, David S. Watt, Lilia M. Kril, Aman Khurana, Fanny Chapelin, Chunming Liu, Joseph B. Zwischenberger, B. Mark Evers, Roberto Gedaly

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Background: Hepatocellular Carcinoma (HCC) is the third most common cause of cancer related death worldwide. Adequate treatment options for patients with advanced HCC are currently limited. Materials and Methods: We studied the anti-HCC effect of FH535 and a novel derivative Y3, on proliferation, mitochondrial function and cellular metabolism focusing on the three key substrates, glutamine, glucose, and fatty acids. Results: FH535 and Y3 disrupted mitochondrial redox control in HCC cells that resulted from uncoupling mechanisms that increased proton leakage and decreased ATP production leading to apoptosis. The uncoupling effects of the sulfonamides in HCC cells were supported by the loss of activity of the methylated analogs. The accumulation of ROS significantly contributed to cell damage after the impaired autophagic machinery. These sulfonamides, FH535 and Y3, targeted glutamine and fatty acid metabolism and caused HCC cell reprograming towards the preferential use of glucose and the glycolytic pathway. Conclusions: FH535, and Y3, demonstrated potent anti-HCC activity by targeting OXPHOS, increasing dangerous levels of ROS and reducing ATP production. These sulfonamides target glutamine and FA metabolic pathways significantly increasing the cellular dependency on glycolysis.

Original languageEnglish
Pages (from-to)3013-3024
Number of pages12
Issue number31
StatePublished - Aug 1 2020

Bibliographical note

Publisher Copyright:
Copyright: © Turcios et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


  • Glutamine metabolism
  • Hepatocellular carcinoma
  • Mitochondria
  • Proton uncouplers
  • Wnt/β-catenin pathway

ASJC Scopus subject areas

  • Oncology


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