Preclinical Evaluation of Dimethyl Itaconate Against Hepatocellular Carcinoma via Activation of the e/iNOS-Mediated NF-κB–Dependent Apoptotic Pathway

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.

Dimethyl itaconate selectively targets inflammatory and metabolic pathways in chronic lymphocytic leukemia

“…The use of DI is currently proposed as a novel putative treatment strategy for several inflammatory-mediated diseases including cardiovascular diseases where a recent report showed that DI-loaded nanofibers reduce inflammation and help to repair myocardic infarction [16,[22][23][24][25]. In the context of cancer, DI showed anticancer activity in mouse models of hepatocellular carcinoma [26] and protected mice from colitis-associated colorectal cancer through its anti-inflammatory effects [27]. A recent report demonstrated an antitumor effect of DI on a thymic carcinoma cell line [28]; however, our data show for the first time as proof of principle a direct therapeutic effect of DI on primary leukemic cells.…”

Theobroma cacao fortified-feed ameliorates potassium bromate-induced oxidative damage in male Wistar rat

“…In either liver or kidney tissue, the groups fed fortified feed led to a restored activity which was a result of Theobroma cacao protection. Urea is a waste product from the amino acid catabolism [61] while creatinine is the by-product of creatine catabolism [62] . The concentration of these products in the serum is regulated by the kidney; hence compromise in its functional status will lead to an increase in the serum.…”

Metabolite itaconate in host immunoregulation and defense

“…Gautam et al. [ 162 ] reported DI is an anticancer drug for diethylnitrosamine-induced hepatocellular carcinoma in albino Wistar rats. Recently, we found 4-OI inhibited aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer in mice models [ 163 ].…”