Xanthatin anti-tumor cytotoxicity is mediated via glycogen synthase kinase-3β and β-catenin.
Xanthatin, a xanthanolide sesquiterpene lactone isolated from Xanthium strumarium L. (Asteraceae), has prominent anti-tumor activity. Initial mechanism of action studies suggested xanthatin triggered activation of Wnt/β-catenin. We examined the effects of xanthatin on signaling pathways in A459 lung cancer cells and mouse embryonic fibroblasts to ascertain requirements for xanthatin-induced cell death and tumor growth in xenografts. Genetic inactivation of GSK-3β, but not the related isoform GSK-3α, compromised xanthatin cytotoxicity while inactivation of β-catenin enhanced xanthatin-mediated cell death. These data provide insight into how xanthatin and related molecules could be effectively targeted toward certain tumors.
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.
Li
L
Tao
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
Xiaobo
X
Sheng
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China; Department of Pharmacy, Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230001, China.
Lei
L
Zhang
Engineering Center of State Ministry of Education for Standardization of Chinese Medicine Processing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
Weidong
W
Li
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
Zhonghong
Z
Wei
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
Pinting
P
Zhu
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
Feng
F
Zhang
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
Aiyun
A
Wang
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1X5, Canada. Electronic address: woodgett@lunenfeld.ca.
James R
JR
Woodgett
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China. Electronic address: luyingreen@njucm.edu.cn.
Yin
Y
Lu
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005663:Furans / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D031210:Xanthium / Q000737:chemistry; D051176:beta Catenin / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D051176:beta Catenin; C022186:xanthatin; D000071679:Glycogen Synthase Kinase 3 beta
GSK-3; Natural compound; Tumor growth; Xanthatin; β-Catenin