Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with more than 800,000 new cases annually [1]
We reported that 2,5-dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535), a sulfonamide that targets this pathway and alters mitochondrial respiration and the autophagic process, is active alone and in combination with other drugs against Hepatocellular Carcinoma (HCC) in vitro and in vivo [17]
We recently reported that FH535 affected the Wnt/β-catenin pathway functioning as a mitochondrial “proton uncoupler” in colon cancer cells
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with more than 800,000 new cases annually [1]. Surgery either liver resection or transplantation are considered the treatment of choice in the early stages of HCC. Most patients present with advanced stages of the disease for which limited treatment options result in dismal 5-year survival in the range of 10% according to the American Cancer Society. Sorafenib, a known multi-kinase inhibitor, became the first-line treatment for advanced-stage HCC, but provided limited improvement in patient survival [2]. 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
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