Inhibitory effects of nobiletin and its major metabolites on lung tumorigenesis
Yue Sun1, Yanhui Han2, Mingyue Song3
1Anhui Engineering Laboratory for Agro-products Processing, State Key Laboratory of Tea Plant Biology and Utilization, International Joint Laboratory on Tea Chemistry and Health Effects, Anhui Agricultural University, Hefei, China and Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA. hangxiao@foodsci.umass.edu.
Abstract:
Nobiletin (NBT), a citrus flavonoid, has been associated with various health benefits. Herein, we investigated the chemopreventive actions of NBT and its metabolites in a pulmonary carcinogenesis mouse model and human lung cancer cells. In 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-treated mice, the oral administration of NBT significantly suppressed lung tumorigenesis as evidenced by reduced tumor volume compared to the control mice. NBT also greatly attenuated cell proliferation in the lung of NNK-treated mice. Our previous study has identified three major metabolites of NBT, namely, 3'-demethylnobiletin (M1), 4'-demethylnobiletin (M2), and 3',4'-didemethylnobiletin (M3). In this study, we further determined the inhibitory effects of NBT and its metabolites on human non-small cell lung cancer (NSCLC) cells and the underlying mechanisms of action. Interestingly, we found that M2 and M3 exerted much stronger growth inhibition on both H460 and H1299 cells, compared to their parent compound NBT. Flow cytometry and western blotting analysis revealed that M2 and M3 caused significant cell cycle arrest and cellular apoptosis and profoundly modulated multiple proteins associated with cell proliferation and cell death, including p21, cyclin B1, CDK1, cyclin D1, CDK6, CDK4, Bax, cleaved caspase-1, and cleaved PARP. Overall, our results demonstrated that the oral administration of NBT significantly inhibited lung carcinogenesis in mice, and these chemopreventive effects could be attributed to its metabolites that showed potent anti-cancer effects.
Insights
Citrus flavonoid nobiletin (NBT) and its metabolites show potent anti-lung cancer effects. NBT suppressed lung tumors in mice, while its metabolites M2 and M3 effectively inhibited human non-small cell lung cancer cell growth.
Area of Science:
- Chemoprevention
- Cancer Biology
- Pharmacology
Background:
- Nobiletin (NBT), a citrus flavonoid, possesses potential health benefits.
- Lung cancer remains a leading cause of cancer-related mortality worldwide.
- Understanding the chemopreventive potential of natural compounds is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the chemopreventive effects of NBT and its metabolites against lung carcinogenesis.
- To evaluate the anti-cancer activity of NBT metabolites on human non-small cell lung cancer (NSCLC) cells.
- To elucidate the underlying mechanisms of action for NBT and its metabolites.
Main Methods:
- A pulmonary carcinogenesis mouse model induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was used.
- NBT was administered orally to NNK-treated mice to assess its effect on lung tumorigenesis.
- Human NSCLC cell lines (H460 and H1299) were treated with NBT and its identified metabolites (M1, M2, M3) to evaluate their inhibitory effects.
- Flow cytometry and western blotting were employed to analyze cell cycle arrest, apoptosis, and protein expression.
Main Results:
- Oral administration of NBT significantly suppressed lung tumorigenesis and reduced tumor volume in NNK-treated mice.
- NBT metabolites, specifically 4'-demethylnobiletin (M2) and 3',4'-didemethylnobiletin (M3), exhibited stronger growth inhibition on NSCLC cells compared to NBT.
- M2 and M3 induced significant cell cycle arrest and apoptosis, modulating key proteins involved in cell proliferation and death (e.g., p21, Bax, cleaved caspase-1).
Conclusions:
- Nobiletin demonstrates significant chemopreventive effects against lung carcinogenesis in a mouse model.
- The anti-cancer activity of NBT is largely attributed to its metabolites, M2 and M3, which possess potent inhibitory effects on NSCLC cells.
- NBT metabolites represent promising candidates for the development of novel lung cancer chemopreventive and therapeutic agents.
