Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors affecting a large population worldwide, with the fifth and seventh greatest mortality rates among men and women, respectively, and the third prime cause of mortality among cancer victims. Dimethyl itaconate (DI) has been reported to be efficacious in colorectal cancer by decreasing IL-1β release from intestinal epithelial cells. In this study, diethylnitrosamine (DEN)-induced HCC in male albino Wistar rats was treated with DI as an anticancer drug. The function and molecular mechanism of DI against HCC in vivo were assessed using histopathology, enzyme-linked immunosorbent assay (ELISA), and Western blot studies. Metabolomics using 1H-NMR was used to investigate metabolic profiles. As per molecular insights, DI has the ability to trigger mitochondrial apoptosis through iNOS- and eNOS-induced activation of the NF-κB/Bcl-2 family of proteins, CytC, caspase-3, and caspase-9 signaling cascade. Serum metabolomics investigations using 1H-NMR revealed that aberrant metabolites in DEN-induced HCC rats were restored to normal following DI therapy. Furthermore, our data revealed that the DI worked as an anti-HCC agent. The anticancer activity of DI was shown to be equivalent to that of the commercial chemotherapeutic drug 5-fluorouracil.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common tumors affecting a large population worldwide, with the fifth and seventh greatest mortality rates among men and women, respectively, and the third leading cause of mortality among cancer victims (Hashimoto et al, 2009)
The molecular mechanism of HCC is still unclear to researchers, finding a new anti-HCC medicine is very challenging
In light of the present HCC therapeutic situation, we suggested Dimethyl itaconate (DI) as an anti-HCC drug for the first time, along with its molecular mode of action
Summary
Hepatocellular carcinoma (HCC) is one of the most common tumors affecting a large population worldwide, with the fifth and seventh greatest mortality rates among men and women, respectively, and the third leading cause of mortality among cancer victims (Hashimoto et al, 2009). Since the molecular pathway of HCC is still unknown to the scientific community, there are very few synthetic drugs available on the market to cure it (Keshari et al, 2017). As the only medication of high preference for HCC therapy, has a poor efficacy and is resistant to various molecular enzymes, making it a poor therapeutic option for the disease (Avila et al, 2006; Giannelli et al, 2014). It has a considerable number of distressing negative effects and is highly overpriced (Kondo et al, 2017). In order to improve HCC treatment options, novel compounds must be discovered and studied
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