The authors declare no conflict of interest.
EGFR inhibitor BIBU induces apoptosis and defective autophagy in glioma cells
Article first published online: 29 JUN 2012
© 2012 Wiley Periodicals, Inc.
Volume 52, Issue 12, pages 970–982, December 2013
How to Cite
Ghildiyal, R., Dixit, D. and Sen, E. (2013), EGFR inhibitor BIBU induces apoptosis and defective autophagy in glioma cells. Mol. Carcinog., 52: 970–982. doi: 10.1002/mc.21938
- Issue published online: 19 NOV 2013
- Article first published online: 29 JUN 2012
- Manuscript Revised: 4 JUN 2012
- Manuscript Accepted: 4 JUN 2012
- Manuscript Received: 12 MAR 2012
- Department of Biotechnology (DBT, Government of India #BT/PR/12924/Med/30/235/2009)
The importance of aberrant EGFR signaling in glioblastoma progression and the promise of EGFR-specific therapies, prompted us to determine the efficacy of novel EGFR inhibitor BIBU-1361 [(3-chloro-4-fluoro-phenyl)-[6-(4-diethylaminomethyl-piperidin-1-yl)-pyrimido [5,4-d]pyrimidin-4-yl]-amine] in affecting glioma survival. BIBU induced apoptosis in a caspase-dependent manner and induced cell cycle arrest in glioma cells. Apoptosis was accompanied by decreased EGFR levels and its increased distribution towards caveolin rich lipid raft microdomains. BIBU inhibited pro-survival pathways Akt/mTOR and gp130/JAK/STAT3; and decreased levels of pro-inflammatory cytokine IL-6. BIBU caused increased LC3-I to LC3-II conversion and triggered the internalization of EGFR within vacuoles along with its increased co-localization with LC3-II. BIBU caused accumulation of p62 and increased levels of cleaved forms of Beclin-1 in all the cell lines tested. Importantly, BIBU failed to initiate execution of autophagy as pharmacological inhibition of autophagy with 3-Methyladenine or Bafilomycin failed to rescue BIBU mediated death. The ability of BIBU to abrogate Akt and STAT3 activation, induce apoptosis and prevent execution of autophagy warrants its investigation as a potent anti-glioma target. © 2012 Wiley Periodicals, Inc.