Mangiferin, a novel nuclear factor kappa B-inducing kinase inhibitor, suppresses metastasis and tumor growth in a mouse metastatic melanoma model.

Abstract

Advanced metastatic melanoma, one of the most aggressive malignancies, is currently without reliable therapy. Therefore, new therapies are urgently needed. Mangiferin is a naturally occurring glucosylxanthone and exerts many beneficial biological activities. However, the effect of mangiferin on metastasis and tumor growth of metastatic melanoma remains unclear. In this study, we evaluated the effect of mangiferin on metastasis and tumor growth in a mouse metastatic melanoma model. We found that mangiferin inhibited spontaneous metastasis and tumor growth. Furthermore, mangiferin suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated NF-κB-inducing kinase (NIK), inhibitor of kappa B kinase (IKK), and inhibitor of kappa B (IκB) and increases the expression of IκB protein in vivo. In addition, we found that mangiferin inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs) in vivo. Mangiferin treatment also increased the expression of cleaved caspase-3, cleaved Poly ADP ribose polymerase-1 (PARP-1), p53 upregulated modulator of apoptosis (PUMA), p53, and phosphorylated p53 proteins, and decreased the expression of Survivin and Bcl-associated X (Bcl-xL) proteins in vivo. These results indicate that mangiferin selectivity suppresses the NF-κB pathway via inhibition of NIK activation, thereby inhibiting metastasis and tumor growth. Importantly, the number of reported NIK selective inhibitors is limited. Taken together, our data suggest that mangiferin may be a potential therapeutic agent with a new mechanism of targeting NIK for the treatment of metastatic melanoma.

• Authors: Tomoya Takeda, Masanobu Tsubaki, Kotaro Sakamoto, Eri Ichimura, Aya Enomoto, Yuri Suzuki, Tatsuki Itoh, Motohiro Imano, Genzoh Tanabe, Osamu Muraoka, Hideaki Matsuda, Takao Satou, Shozo Nishida
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 306 Pg. 105-12 (09 01 2016) ISSN: 1096-0333 [Electronic] United States
• PMID: 27417526 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Integrins
• Protein Kinase Inhibitors
• RNA, Messenger
• Xanthones
• mangiferin
• Protein Serine-Threonine Kinases
• Matrix Metalloproteinases

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis Regulatory Proteins (metabolism)
• Integrins (genetics)
• Male
• Matrix Metalloproteinases (genetics)
• Melanoma, Experimental (drug therapy, metabolism, pathology)
• Mice, Inbred C57BL
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• RNA, Messenger (metabolism)
• Xanthones (pharmacology, therapeutic use)
• NF-kappaB-Inducing Kinase