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- W4210381479 abstract "Abstract Background Human hepatocellular carcinoma (HCC) is an aggressive malignancy worldwide with a poor clinical outcome. There are limited therapeutic options currently available for those diagnosed with terminal HCC and therefore incorporating novel agents into standard-of-care regimens is urgently needed. In contrast to de novo drug discovery, the strategy of repurposing already-approved compounds initially designed to treat animals, which share similarities in disease-associated characteristics with humans ( i.e. , dogs), might yield substantial advantages in terms of efficacy and safety. Given the evidence for clinical efficacy of toceranib phosphate (TOC) against canine carcinomas, we aimed to investigate its potential therapeutic effects on human HCC and the mechanisms involved. Methods We evaluated the antitumor effects of TOC using human HCC cell-line and cell line-derived xenograft models. Changes in autophagic response upon TOC exposure were quantified through immunoblotting and immunofluorescence analysis. The role of TOC-triggered autophagy was addressed via pharmacological and genetic inhibition. Results TOC, an approved canine drug, exhibited potent antitumor activity against human HCC cells by stimulating apoptosis in vitro and in vivo , which was accompanied by a concomitant increase in autophagic flux. Artificially blocking the TOC-triggered autophagy, either by pharmacologically using autophagy inhibitors or genetic interference, significantly inhibited cellular proliferation in vitro and decreased tumor burden in vivo , indicating a protective role of autophagy against TOC-mediated HCC cell death. This role played by TOC-induced autophagy was further linked to the inactivation of Akt/mTOR pathway that can be largely attributed to the upregulation of matricellular protein Cyr61 in HCC cells. Moreover, in vivo and in vitro treatment with standard systemic therapeutic sorafenib plus TOC resulted in pronounced synergistic effects on HCC cells. Conclusions Our results elucidate a newly identified therapeutic potential of TOC in treating HCC, sparking a growing interest in repurposing such canine drugs for human use." @default.
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- W4210381479 date "2022-01-31" @default.
- W4210381479 modified "2023-10-16" @default.
- W4210381479 title "Discovery of Canine Drug Toceranib Phosphate as a Repurposed Agent against Human Hepatocellular Carcinoma" @default.
- W4210381479 doi "https://doi.org/10.21203/rs.3.rs-1298194/v1" @default.
- W4210381479 hasPublicationYear "2022" @default.
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