Abstract:
:Cyclin dependent kinase (CDK) inhibitors, such as flavopiridol, demonstrate significant single-agent activity in chronic lymphocytic leukemia (CLL), but the mechanism of action in these nonproliferating cells is unclear. Here we demonstrate that CLL cells undergo autophagy after treatment with therapeutic agents, including fludarabine, CAL-101, and flavopiridol as well as the endoplasmic reticulum (ER) stress-inducing agent thapsigargin. The addition of chloroquine or siRNA against autophagy components enhanced the cytotoxic effects of flavopiridol and thapsigargin, but not the other agents. Similar to thapsigargin, flavopiridol robustly induces a distinct pattern of ER stress in CLL cells that contributes to cell death through IRE1-mediated activation of ASK1 and possibly downstream caspases. Both autophagy and ER stress were documented in tumor cells from CLL patients receiving flavopiridol. Thus, CLL cells undergo autophagy after multiple stimuli, including therapeutic agents, but only with ER stress mediators and CDK inhibitors is autophagy a mechanism of resistance to cell death. These findings collectively demonstrate, for the first time, a novel mechanism of action (ER stress) and drug resistance (autophagy) for CDK inhibitors, such as flavopiridol in CLL, and provide avenues for new therapeutic combination approaches in this disease.
journal_name
Bloodjournal_title
Bloodauthors
Mahoney E,Lucas DM,Gupta SV,Wagner AJ,Herman SE,Smith LL,Yeh YY,Andritsos L,Jones JA,Flynn JM,Blum KA,Zhang X,Lehman A,Kong H,Gurcan M,Grever MR,Johnson AJ,Byrd JCdoi
10.1182/blood-2011-12-400184subject
Has Abstractpub_date
2012-08-09 00:00:00pages
1262-73issue
6eissn
0006-4971issn
1528-0020pii
blood-2011-12-400184journal_volume
120pub_type
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