title: 3,6,2',4',5'-Pentahydroxyflavone, an orally bioavailable multiple protein kinase inhibitor, overcomes gefitinib resistance in non-small cell lung cancer.
abstract: Non-small cell lung cancer (NSCLC) is the most lethal cancer, causing more than 150,000 deaths in the United States in 2013. The receptor tyrosine kinase inhibitors such as gefitinib are not perfect clinical therapeutic agents for NSCLC treatment due to primary or acquired tyrosine kinase inhibitor resistance. Herein, 3,6,2',4',5'-pentahydroxyflavone (36245-PHF) was identified as a multiple kinase inhibitor for NSCLC treatment based on the computational screening of a natural products database. 36245-PHF was shown to inhibit PI3K and Aurora A and B kinases and overcome gefitinib-resistant NSCLC growth. Our data clearly showed that 36245-PHF markedly inhibited anchorage-independent growth of gefitinib-resistant NSCLC cell lines and exerted a substantial chemotherapeutic effect following oral administration in a gefitinib-resistant NSCLC xenograft model. The evidence from three different subsequent methodological approaches, in vitro, ex vivo, and in vivo, all confirmed that 36245-PHF as a multiple protein kinase inhibitor. Overall, we identified 36245-PHF as a multiple protein kinase inhibitor and as a novel therapeutic agent to overcome gefitinib-resistant NSCLC growth, which could provide a new option for clinical NSCLC oral treatment.
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, the Department of Physiology and Pathophysiology, Basic Medical College, Zhengzhou University, Henan 450001, China, and The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450001, China, and.
authors.forename: Yuqiao
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, the Cancer Research Institute, Xiangya School of Medicine and.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, the Department of Physiology and Pathophysiology, Basic Medical College, Zhengzhou University, Henan 450001, China, and.
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912.
authors.forename: Ke
authors.initials: K
authors.lastname: Yao
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912.
authors.forename: Kanamata
authors.initials: K
authors.lastname: Reddy
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Lim
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912.
authors.forename: Naomi
authors.initials: N
authors.lastname: Oi
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Peng
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912.
authors.forename: Wei-Ya
authors.initials: WY
authors.lastname: Ma
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: the Department of Physiology and Pathophysiology, Basic Medical College, Zhengzhou University, Henan 450001, China, and Dongzm@zzu.edu.cn.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Dong
authors.affiliation: From the The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, zgdong@hi.umn.edu.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D005419:Flavonoids; D000077156:Gefitinib; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C008775:peflavit; C576917:AURKA protein, human; C576921:AURKB protein, human
keywords: Aurora Kinase; Flavonoid; Gefitinib Resistance; Lung Cancer; Multikinase Inhibitor; NSCLC; P13K; Protein Kinase; Receptor Tyrosine Kinase; Signal Transduction