Development of a bifunctional andrographolide-based chemical probe for pharmacological study
Journal
PLoS ONE
Journal Volume
11
Journal Issue
4
Pages
e0152770
Date Issued
2016
Author(s)
Abstract
Andrographolide (ANDRO) is a lactone diterpenoid compound present in the medicinal plant Andrographis paniculata which is clinically applied for multiple human diseases in Asia and Europe. The pharmacological activities of andrographolide have been widely demonstrated, including anti-inflammation, anti-cancer and hepatoprotection. However, the pharmacological mechanism of andrographolide remains unclear. Therefore, further characterization on the kinetics and molecular targets of andrographolide is essential. In this study, we described the synthesis and characterization of a novel fluorescent andrographolide derivative (ANDRO-NBD). ANDRO-NBD exhibited a comparable anti-cancer spectrum to andrographolide: ANDRO-NBD was cytotoxic to various types of cancer cells and suppressed the migration activity of melanoma cells; ANDRO-NBD treatment induced the cleavage of heat shock protein 90 (Hsp90) and the downregulation of its client oncoproteins, v-Src and Bcr-abl. Notably, ANDRO-NBD showed superior inhibitory effects to andrographolide in all anticancer assays we have performed. In addition, ANDRO-NBD was further used as a fluorescent probe to investigate the uptake kinetics, cellular distribution and molecular targets of andrographolide. Our data revealed that ANDRO-NBD entered cells rapidly and its fluorescent signal could be detected in nucleus, cytoplasm, mitochondria, and lysosome. Moreover, we demonstrated that ANDRO-NBD was covalently bound to several putative target proteins of andrographolide, including NF-?B and hnRNPK. In summary, we developed a fluorescent andrographolide probe with comparable bioactivity to andrographolide, which serves as a powerful tool to explore the pharmacological mechanism of andrographolide. ? 2016 Hsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
SDGs
Other Subjects
andrographolide; andrographolide nbd; antineoplastic agent; BCR ABL protein; diterpenoid; fluorescent dye; heat shock protein 90; heterogeneous nuclear ribonucleoprotein K; immunoglobulin enhancer binding protein; protein tyrosine kinase; unclassified drug; andrographolide; diterpene; molecular probe; Article; cell nucleus; cellular distribution; controlled study; covalent bond; cytoplasm; drug cytotoxicity; drug structure; drug synthesis; human; human cell; lysosome; melanoma cell; migration inhibition; mitochondrion; protein cleavage; adult; chemistry; female; male; middle aged; molecular probe; nuclear magnetic resonance imaging; Adult; Diterpenes; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Molecular Probes
Type
journal article