title: Radicol, a Novel Trinorguaiane-Type Sesquiterpene, Induces Temozolomide-Resistant Glioma Cell Apoptosis via ER Stress and Akt/mTOR Pathway Blockade.
abstract: Glioblastoma multiforme (GBM) is the most frequent, lethal and aggressive tumour of the central nervous system (CNS) in adults. Multidrug resistance (MDR) results in undesirable prognosis during GBM chemotherapy. In this study, we determined that Radicol (RAD), a novel trinorguaiane-type sesquiterpene originally isolated from the root of Dictamnus radicis Cortex, exhibited potently cytotoxic effect on temozolomide (TMZ)-resistant GBM cell lines in a dose-dependent manner. Radicol-induced apoptosis was confirmed with Hoechst 33342/propidium iodide and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labelling (TUNEL) staining. Studies investigating the mechanism revealed that RAD triggered an attenuation of protein disulphide isomerase (PDI) and induced the unmitigated unfolded protein response (UPR) and lethal endoplasmic reticulum (ER) stress. Simultaneously, we further demonstrated that RAD suppressed the activation of Akt/mTOR/p70S6K phosphorylation by up-regulating the induction of glycogen synthase kinase-3β (GSK-3β). These results established a link between RAD-induced ER stress and inhibition of the Akt/mTOR/p70S6K pathway, and the attenuation of PDI and activation of GSK-3β might be the synergistic target of antineoplastic effects during RAD-induced apoptosis. These findings suggested that RAD, possessing multiple cytotoxicity targets, low molecular weight and high lipid solubility, could be a promising agent for the treatment of malignant gliomas. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.|Shenzhen Key Laboratory of Neurosurgery, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.
authors.forename: Zong-Yang
authors.initials: ZY
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.|Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, China.
authors.forename: Ce
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.|Shenzhen Key Laboratory of Neurosurgery, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.|Shenzhen Key Laboratory of Neurosurgery, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.
authors.forename: Bao-Dong
authors.initials: BD
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.|Shenzhen Key Laboratory of Neurosurgery, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.
authors.forename: Qing-Zhong
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.|Shenzhen Key Laboratory of Neurosurgery, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.
authors.forename: Xie-Jun
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.|Shenzhen Key Laboratory of Neurosurgery, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D036905:Dictamnus / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy; D005910:Glioma / Q000473:pathology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D010766:Phosphorylation / Q000187:drug effects; D008517:Phytotherapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D012717:Sesquiterpenes; C528839:radicol; D003606:Dacarbazine; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D000077204:Temozolomide
keywords: Akt/mTOR; ER stress; GSK-3β; PDI; radicol; temozolomide resistant