Published online Dec 7, 2020. doi: 10.3748/wjg.v26.i45.7131
Peer-review started: July 25, 2020
First decision: September 14, 2020
Revised: September 28, 2020
Accepted: November 12, 2020
Article in press: November 12, 2020
Published online: December 7, 2020
Worldwide, hepatocellular carcinoma (HCC) is a prevalent lethal disease exhibiting the highest cancer mortality rate with limited chemotherapeutic options. The discovery of a new chemotherapeutic agent is an urgent demand for the treatment of HCC patients.
Tight Junction (TJ) proteins have been implicated to regulate various signal transductions in carcinogenesis. Recent evidence has shown that nimbolide possesses anticancer activity in various cancers; however, its specific mechanism in HCC remains elusive.
We aimed to study the effect of nimbolide on TJ proteins, cell cycle progression, and hepatic inflammation in an experimental hepatocarcinogenesis mouse model.
Diethylnitrosamine (DEN) and N-nitrosomorpholine (NMOR) induced mouse model of HCC was performed in the present study. Nimbolide was given orally for four consecutive weeks to DEN/NMOR induced HCC mice from 28th to 32nd week. At the end of the study period (32nd week), all the mice were sacrificed, blood and liver samples were collected for various analysis. HCC tumor markers such as alpha-fetoprotein (AFP) levels and glypican-3 protein expression were analysed. Hepatic TJ proteins, cell cycle, and inflammatory marker protein expressions were evaluated by western blot analysis. Cell proliferation and oxidative stress markers were analyzed by immunohistochemistry. Molecular docking study was performed to confirm the interaction of nimbolide with zonula occludens 1 (ZO-1), nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) and tumor necrosis factor alpha (TNF-α).
Hepatic tumor size and HCC tumor markers AFP and glypican-3 were reduced following nimbolide treatment. TJ protein (ZO-1 and occludin) expression levels were restored after nimbolide treatment, while ZO-1 associated nucleic acid binding protein expression was attenuated. Additionally, nimbolide treatment also reduced cell proliferation and cell cycle markers. Moreover, nimbolide treatment ameliorated hepatic inflammation and oxidative stress in HCC mice. The binding affinity and modulatory effects of nimbolide with ZO-1, NF-κB, and TNF-α were confirmed by molecular docking analysis.
Nimbolide treatment showed anticancer effects by improving TJ proteins expression, suppressing cell cycle and cell proliferation, and ameliorating inflammation and oxidative stress in DEN and NMOR induced HCC mice.
Nimbolide may be used as a potential chemotherapeutic agent for HCC treatment. Further molecular research and human studies may delineate nimbolide as a candidate drug for HCC treatment.