Document Detail

Obatoclax and lapatinib interact to induce toxic autophagy through NOXA.
MedLine Citation:
PMID:  22219388     Owner:  NLM     Status:  MEDLINE    
Prior studies demonstrated that resistance to the ERBB1/2 inhibitor lapatinib could be overcome by the B cell CLL/lymphoma-2 (BCL-2) family antagonist obatoclax (GX15-070). Coadministration of lapatinib with obatoclax caused synergistic cell killing by eliciting autophagic cell death that was dependent upstream on mitochondrial reactive oxygen species generation and increased p62 levels and downstream on activation of p38 mitogen-activated protein kinase and inactivation of mammalian target of rapamycin. By immunohistochemical analysis, in drug combination-treated cells, microtubule-associated protein light chain 3 (LC3) associated with mitochondrial (cytochrome c oxidase), autophagosome (p62), and autolysosome (lysosomal associated membrane protein 2) proteins. Treatment of cells with 3-methyladenine or knockdown of beclin 1 was protective, whereas chloroquine treatment had no protective effect. Expression of myeloid cell leukemia-1 (MCL-1), compared with that of BCL-2 or BCL-2-related gene long isoform, protected against drug combination lethality. Lapatinib and obatoclax-initiated autophagy depended on NOXA-mediated displacement of the prosurvival BCL-2 family member, MCL-1, from beclin 1, which was essential for the initiation of autophagy. Taken together, our data argue that lapatinib and obatoclax-induced toxic autophagy is due to impaired autophagic degradation, and this disturbance of autophagic flux leads to an accumulation of toxic proteins and loss of mitochondrial function.
Yong Tang; Hossein A Hamed; Nichola Cruickshanks; Paul B Fisher; Steven Grant; Paul Dent
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-01-04
Journal Detail:
Title:  Molecular pharmacology     Volume:  81     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-19     Completed Date:  2012-05-07     Revised Date:  2013-12-09    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  527-40     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Agents / pharmacology*
Autophagy / drug effects*
Cell Death
Cell Line, Tumor
Genes, erbB-2
Proto-Oncogene Proteins c-bcl-2 / physiology*
Pyrroles / pharmacology*
Quinazolines / pharmacology*
Grant Support
CA141703/CA/NCI NIH HHS; CA150218/CA/NCI NIH HHS; DK52825/DK/NIDDK NIH HHS; F32-CA85159/CA/NCI NIH HHS; R01 CA127641-04/CA/NCI NIH HHS; R01 CA134721-04/CA/NCI NIH HHS; R01 CA141703/CA/NCI NIH HHS; R01 CA150214/CA/NCI NIH HHS; R01 DK052825/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrroles; 0/Quinazolines; 0/obatoclax; 0VUA21238F/lapatinib

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