Purine-Type Compounds Induce Microtubule Fragmentation and Lung Cancer Cell Death through Interaction with Katanin

Ting Chun Kuo, Ling Wei Li, Szu Hua Pan, Jim Min Fang, Jyung Hurng Liu, Ting Jen Cheng, Chia Jen Wang, Pei Fang Hung, Hsuan Yu Chen, Tse Ming Hong, Yuan Ling Hsu, Chi Huey Wong, Pan Chyr Yang

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Microtubule targeting agents (MTAs) constitute a class of drugs for cancer treatment. Despite many MTAs have been proven to significantly improve the treatment outcomes of various malignancies, resistance has usually occurred. By selection from a two million entry chemical library based on the efficacy and safety, we identified purine-type compounds that were active against lung small cell lung cancer (NSCLC). The purine compound 5a (GRC0321) was an MTA with good effects against NSCLC. Lung cancer cells H1975 treated with 5a could induce microtubule fragmentation, leading to G2/M cell cycle arrest and intrinsic apoptosis. Compound 5a directly targeted katanin and regulated the severing activity of katanin, which cut the cellular microtubules into short pieces and activated c-Jun N-terminal kinases (JNK). The microtubule fragmenting effect of 5a is a unique mechanism in MTAs. It might overcome the resistance problems that most of the MTAs have faced.

Original languageEnglish
Pages (from-to)8521-8534
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number18
DOIs
Publication statusPublished - 2016 Sept 22

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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