Mechanistic and therapeutic study of novel anti-tumor function of natural compound imperialine for treating non-small cell lung cancer.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Bulbus Fritillaria cirrhosa D. Don (BFC) is a Chinese traditional herbal medicine that has long been used as an indispensable component in herbal prescriptions for bronchopulmonary diseases due to its well-established strong anti-inflammation and pulmonary harmonizing effects. Interestingly, there are few case reports in traditional Chinese medicine available where they found it to contribute in anti-tumor therapies. Imperialine is one of the most favored active substances extracted from BFC and has been widely recognized as an anti-inflammatory agent.

AIM OF THE STUDY:

The aim of the current work is to provide first-hand evidences both in vitro and in vivo showing that imperialine exerts anti-cancer effects against non-small cell lung cancer (NSCLC), and to explore the molecular mechanism of this anti-tumor activity. It is also necessary to examine its systemic toxicity, and to investigate how to develop strategies for feasible clinical translation of imperialine.

MATERIALS AND METHODS:

To investigate anti-NSCLC efficacy of imperialine using both in vitro and in vivo methods where A549 cell line were chosen as in vitro model NSCLC cells and A549 tumor-bearing mouse model was constructed for in vivo study. The detailed underlying anti-cancer mechanism has been systematically explored for the first time through a comprehensive set of molecular biology methods mainly including immunohistochemistry, western blot and enzyme-linked immunosorbent assays. The toxicity profile of imperialine treatments were evaluated using healthy nude mice by examining hemogram and histopathology. An imperialine-loaded liposomal drug delivery system was developed using thin film hydration method to evaluate target specific delivery.

RESULTS:

The results showed that imperialine could suppress both NSCLC tumor and associated inflammation through an inflammation-cancer feedback loop in which NF-κB activity was dramatically inhibited by imperialine. The NSCLC-targeting liposomal system was successfully developed for targeted drug delivery. The developed platform could favorably enhance imperialine cellular uptake and in vivo accumulation at tumor sites, thus improving overall anti-tumor effect. The toxicity assays revealed imperialine treatments did not significantly disturb blood cell counts in mice or exert any significant damage to the main organs.

CONCLUSIONS:

Imperialine exerts anti-cancer effects against NSCLC both in vitro and in vivo, and this previously unknown function is related to NF-κB centered inflammation-cancer feedback loop. Imperialine mediated anti-cancer activity is not through cytotoxicity and exhibit robust systemic safety. Furthermore, the liposome-based system we commenced would dramatically enhance therapeutic effects of imperialine while exhibiting extremely low side effects both on cellular and in NSCLC model. This work has identified imperialine as a promising novel anti-cancer compound and offered an efficient target-delivery solution that greatly facilitate practical use of imperialine.

• Authors: Qing Lin, Mengke Qu, Hirak K Patra, Shanshan He, Luyao Wang, Xun Hu, Linyu Xiao, Yu Fu, Tao Gong, Qin He, Ling Zhang, Xun Sun, Zhirong Zhang
• Journal: Journal of ethnopharmacology (J Ethnopharmacol) Vol. 247 Pg. 112283 (Jan 30 2020) ISSN: 1872-7573 [Electronic] Ireland
• PMID: 31605736 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Alkaloids
• Cevanes
• Drugs, Chinese Herbal
• Liposomes
• NF-kappa B
• peiminine

Topics

• A549 Cells
• Alkaloids (administration & dosage, adverse effects, chemistry, isolation & purification)
• Animals
• Blood Cell Count
• Carcinoma, Non-Small-Cell Lung (drug therapy, immunology, pathology)
• Cevanes (administration & dosage, adverse effects, chemistry, isolation & purification)
• Drugs, Chinese Herbal (administration & dosage, adverse effects, chemistry, isolation & purification)
• Feedback, Physiological (drug effects)
• Fritillaria (chemistry)
• Humans
• Liposomes
• Lung Neoplasms (drug therapy, immunology, pathology)
• Male
• Mice
• NF-kappa B (antagonists & inhibitors, immunology)
• Toxicity Tests
• Xenograft Model Antitumor Assays