Sorafenib and FH535 in combination act synergistically on hepatocellular carcinoma by targeting cell bioenergetics and mitochondrial function

Turcios, Lilia; Vilchez, Valery; Acosta, Luis F.; Pratheeshkumar, Poyil; Butterfield, D. Allan; Mitov, Mihail I.; Martí, Francesc; Gedaly, Roberto

doi:10.1016/j.dld.2017.01.146

Cited by 24 publications

(28 citation statements)

References 25 publications

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“…FH535, a β‐catenin/Tcf inhibitor, not only increased radio‐sensitivity but also suppressed EMT in the radioresistant KYSE‐150R esophageal cancer cell line, which indicated that inhibitors of the Wnt signaling pathway might be effective anticancer agents with the potential to be anticancer drugs . In addition, it was reported that FH535 alleviated multiple types of cancer, including colorectal cancer, gastric cancer, and hepatocellular carcinoma . Isoquercitrin, a bioactive flavonoid from Bidens bipinnata L. , inhibited the Wnt/β‐catenin signaling pathway and hepatocyte growth factor/scatter factor‐induced EMT in NBT‐II cells .…”

Section: Small Molecules Against Emtmentioning

confidence: 99%

“…65 In addition, it was reported that FH535 alleviated multiple types of cancer, including colorectal cancer, gastric cancer, and hepatocellular carcinoma. [143][144][145] Isoquercitrin, a bioactive flavonoid from Bidens bipinnata L., inhibited the Wnt/β-catenin signaling pathway and hepatocyte growth factor/scatter factor-induced EMT in NBT-II cells. 146 In addition, salinomycin was previously used as an antibiotic and also showed significant anticancer activity by suppressing EMT.…”

Section: Wnt Signaling Pathwaymentioning

confidence: 99%

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Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Feng

Chen

Vaziri

et al. 2019

Medicinal Research Reviews

104

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Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial‐mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc‐finger E‐box‐binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor‐β1, RAC‐α serine/threonine‐protein kinase, Wnt, nuclear factor‐kappa B, peroxisome proliferator‐activated receptor, Notch, and RAS), RNA‐binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

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Section: Small Molecules Against Emtmentioning

confidence: 99%

Section: Wnt Signaling Pathwaymentioning

confidence: 99%

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Feng

Chen

Vaziri

et al. 2019

Medicinal Research Reviews

104

View full text Add to dashboard Cite

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“…Previous results demonstrated the synergistic inhibitory effect of the combination of FH535 and sorafenib on the proliferation of hepatoma cell lines and liver cancer stem cells [5,9]. While FH535 preferentially targeted mitochondrial respiration, sorafenib preferentially decreased the glycolytic capacity of the cells.…”

Section: Effect In the Glycolytic Ratementioning

confidence: 94%

“…While FH535 preferentially targeted mitochondrial respiration, sorafenib preferentially decreased the glycolytic capacity of the cells. The synergistic actions of both drugs precluded cellular compensation for the energetic imbalance using either glycolysis or the mitochondrial ATP synthesis pathway as sources of ATP production [9].…”

Section: Effect In the Glycolytic Ratementioning

confidence: 99%

“…Because to the lack of treatment options in advanced cases, our group and others have developed strategies using small-molecules targeting different pathways with or without immunotherapy for late stages in pre-clinical or clinical studies [3][4][5][6][7][8][9][10][11]. The Wnt/βcatenin pathway is critical for HCC cell proliferation, progression and stemness, and this pathway is aberrant in 30-50% of the HCC tumors [12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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CD24 targeting bi-specific antibody that simultaneously stimulates NKG2D enhances the efficacy of cancer immunotherapy

Han

Sun

Zhang

et al. 2019

J Cancer Res Clin Oncol

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Sorafenib and FH535 in combination act synergistically on hepatocellular carcinoma by targeting cell bioenergetics and mitochondrial function

Cited by 24 publications

References 25 publications

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

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

CD24 targeting bi-specific antibody that simultaneously stimulates NKG2D enhances the efficacy of cancer immunotherapy

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