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.
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.
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong, China.
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Zhu
authors.forename: Blenda Chi Kwan
authors.initials: BC
authors.lastname: Wong
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
authors.forename: Zhao-Xiang
authors.initials: ZX
authors.lastname: Bian
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Hu-Biao
authors.initials: HB
authors.lastname: Chen
authors.forename: Yuen Fan
authors.initials: YF
authors.lastname: Wong
authors.forename: Wang-Fun
authors.initials: WF
authors.lastname: Fong
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D031644:Ardisia / Q000737:chemistry*; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D018384:Oxidative Stress; D010636:Phenols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D017931:DNA Primers; D010636:Phenols