Document Detail

Autophagy and ER stress play an essential role in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol.
MedLine Citation:
PMID:  23422081     Owner:  NLM     Status:  MEDLINE    
Chronic lymphocytic leukemia (CLL) is a mature B cell malignancy and is the most prevalent type of leukemia in adults. There is no curative therapy for this disease; however, several new agents have shown very promising results. Autophagy has not been studied in CLL and in this study we first sought to determine if autophagy was functional in CLL with classic inducers, and if this contributes to direct cytotoxicity or protection from cell death. While autophagy is activated with all classic stimuli of this process, only unfolded protein endoplasmic reticulum (ER) stress-mediated autophagy protects from cell death. Interestingly, select therapeutic agents (fludarabine, GS-1101, flavopiridol), which are active in CLL, also induce autophagy. Of interest, only the broad cyclin-dependent kinase inhibitor flavopiridol has improved efficacy when autophagy is antagonized biochemically (chloroquine) or by siRNA. This promoted an investigation which demonstrated unexpectedly that flavopiridol mediates ER stress and downstream activation of MAP3K5/ASK1, which ultimately is responsible for cell death. Similarly, autophagy activated in part via ER stress and also CDK5 inhibition is protective against cell death induced by this process. Collectively, our studies demonstrate that in CLL, autophagy is induced by multiple stimuli but only acts as a mechanism of resistance against ER stress-mediating agents. Similarly, flavopiridol mediates ER stress as a primary mechanism of action in CLL, and autophagy serves as a mechanism of resistance to this agent.
Emilia Mahoney; John C Byrd; Amy J Johnson
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Autophagy     Volume:  9     ISSN:  1554-8635     ISO Abbreviation:  Autophagy     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-20     Completed Date:  2013-09-23     Revised Date:  2014-03-03    
Medline Journal Info:
Nlm Unique ID:  101265188     Medline TA:  Autophagy     Country:  United States    
Other Details:
Languages:  eng     Pagination:  434-5     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Agents / pharmacology
Caspases, Initiator / metabolism
Cell Line, Tumor
Chloroquine / pharmacology
Cyclin-Dependent Kinase 5 / metabolism
Cyclin-Dependent Kinases / antagonists & inhibitors,  metabolism*
Drug Resistance*
Endoplasmic Reticulum Stress*
Flavonoids / pharmacology*
Gene Expression Regulation, Leukemic*
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
MAP Kinase Kinase Kinase 5 / metabolism
Piperidines / pharmacology*
Protein Folding
RNA, Small Interfering / metabolism
Grant Support
P01 CA081534/CA/NCI NIH HHS; P30 CA016058/CA/NCI NIH HHS; T32 CA009338/CA/NCI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/Flavonoids; 0/Piperidines; 0/RNA, Small Interfering; 45AD6X575G/alvocidib; 886U3H6UFF/Chloroquine; EC protein, human; EC Kinase 5; EC Kinases; EC Kinase Kinase Kinase 5; EC protein, human; EC 3.4.22.-/CASP4 protein, human; EC 3.4.22.-/Caspases, Initiator

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