Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Title

Alkylphenols from the roots of ardisia brevicaulis induce G1 arrest and apoptosis through endoplasmic reticulum stress pathway in human non-small-cell lung cancer cells

Language

English

Abstract

From the roots of Ardisia brevicaulis DIELS, two new alkylphenol derivatives, named ardisiphenol E (2) and F (3), have been isolated together with a known alkylphenol, ardisiphenol D (1). The structures of 1-3 were elucidated by chemical and spectroscopic techniques. Compounds 1 and 2 exhibited strong cytotoxicities on two human non-small-cell lung cancer cell lines (H1299 and A549). We found that compounds 1 and 2 upregulated mRNA and protein expressions of endoplasmic reticulum (ER) stress markers including C/EBP homologous protein (CHOP), binding immunoglobulin protein (Bip) and inositol-requiring enzyme 1 (IRE1) indicating 1 and 2 are novel natural ER stress inducers. Treatments with 1 and 5 μM of 1 or 2 triggered G1 arrest in H1299 and A549 cells with concomitant downregulation of ubiquitin fusion degradation protein 1 (Ufd1) and S-phase kinase-associated protein 2 (Skp2) proteins and the accumulation of p27, the key axes of ER stress-mediated G1 arrest. Compounds 1 and 2 also induced apoptosis at high concentrations (10, 20 μM) which was shown to be coupled with the upregulation of CHOP and Bim, the activation of caspase-9, caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage. These results indicate that compounds 1 and 2 induce ER stress that subsequently causes G1 arrest and apoptosis in human non-small-cell lung cancer cells and they may have potential anticancer effects. © 2012 The Pharmaceutical Society of Japan.

Keywords

Alkylphenol, Ardisia brevicaulis, Endoplasmic reticulum stress, Human non-small-cell lung cancer, Myrsinaceae

Publication Date

2012

Source Publication Title

Chemical and Pharmaceutical Bulletin

Volume

60

Issue

8

Start Page

1029

End Page

1036

Publisher

Pharmaceutical Society of Japan

DOI

10.1248/cpb.c12-00302

Link to Publisher's Edition

http://dx.doi.org/10.1248/cpb.c12-00302

ISSN (print)

00092363

ISSN (electronic)

13475223

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