Sorafenib effect on liver neoplastic changes in rats: more than a kinase inhibitor
Nahla E El-Ashmawy1, Eman G Khedr1, Hoda A El-Bahrawy1
1Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
Abstract:
Although sorafenib was approved as antiangiogenic agent in case of hepatocellular carcinoma (HCC), the pathways mediating its antitumorigenic effects were not fully examined in vivo. This study was conducted to elucidate the molecular mechanisms underlying the antineoplastic effect of sorafenib in livers of rats exposed to the hepatocarcinogen diethyl nitrosamine (DENA) regarding oxidative stress, proliferation, and apoptotic pathways. Male albino rats were divided into three groups: normal control, DENA group, and sorafenib group. Sorafenib (10 mg/kg) was given daily to rats orally for 2 weeks, started 6 weeks after DENA (200 mg/kg, single i.p. dose). The histopathological results proved that sorafenib corrected neoplastic changes in the liver as evidenced by a decrease in size of hepatocellular foci. The liver index, glutathione, as well as Bcl-2 were significantly decreased in sorafenib group compared with DENA group. Sorafenib also exhibited antiproliferative effect through suppression of gene expression of cyclin D1 and β-catenin. Thus, the apoptotic and proliferative pathways in HCC could be interrupted by sorafenib, supporting the role of sorafenib as antineoplastic agent and nominating it as a candidate drug for other neoplasms.
Insights
Sorafenib treatment reduced liver damage and tumor growth in rats exposed to a carcinogen. It works by affecting cell death and proliferation pathways, supporting its use against liver cancer.
Area of Science:
- Hepatocellular carcinoma (HCC) research
- Molecular mechanisms of cancer therapy
- Oxidative stress and apoptosis
Background:
- Sorafenib is an approved antiangiogenic drug for hepatocellular carcinoma (HCC).
- Its complete antitumorigenic mechanisms in vivo require further elucidation.
- Understanding these pathways can optimize HCC treatment strategies.
Purpose of the Study:
- To investigate the molecular mechanisms of sorafenib's antineoplastic effect in a rat model of HCC.
- To examine the impact of sorafenib on oxidative stress, proliferation, and apoptosis in DENA-induced liver cancer.
- To elucidate the role of sorafenib in modulating key signaling pathways in HCC.
Main Methods:
- Rats were divided into control, diethyl nitrosamine (DENA)-induced HCC, and sorafenib-treated groups.
- Sorafenib (10 mg/kg) was administered orally for two weeks post-DENA exposure.
- Histopathology, liver index, glutathione levels, Bcl-2 expression, and gene expression of cyclin D1 and β-catenin were analyzed.
Main Results:
- Sorafenib treatment corrected neoplastic changes and reduced hepatocellular foci size.
- Significant decreases in liver index, glutathione, and Bcl-2 were observed in the sorafenib group.
- Sorafenib suppressed cyclin D1 and β-catenin gene expression, indicating antiproliferative effects.
Conclusions:
- Sorafenib effectively interrupts apoptotic and proliferative pathways in hepatocellular carcinoma.
- These findings support sorafenib's role as an antineoplastic agent in HCC.
- Sorafenib shows potential as a candidate drug for other neoplasms.
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