3,6,2',4',5'-pentahydroxyflavone, an orally bioavailable multiple protein kinase inhibitor, overcomes gefitinib resistance in non-small cell lung cancer

Yuqiao Sheng, Wei Li, Feng Zhu, Kangdong Liu, Hanyong Chen, Ke Yao, Kanamata Reddy, Do Young Lim, Naomi Oi, Haitao Li, Cong Peng, Wei Ya Ma, Ann M. Bode, Ziming Dong, Zigang Dong

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 gefitinibresistant NSCLC growth, which could provide a new option for clinical NSCLC oral treatment.

Original languageEnglish (US)
Pages (from-to)28192-28201
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number41
DOIs
StatePublished - Oct 10 2014

Bibliographical note

Publisher Copyright:
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

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