title: ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol.
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.
authors: Division of Hematology, Department of Internal Medicine, College of Pharmacy, The Ohio State University (OSU), Columbus, OH 43210, USA.
authors: Emilia
authors: E
authors: Mahoney
authors: David M
authors: DM
authors: Lucas
authors: Sneha V
authors: SV
authors: Gupta
authors: Amy J
authors: AJ
authors: Wagner
authors: Sarah E M
authors: SE
authors: Herman
authors: Lisa L
authors: LL
authors: Smith
authors: Yuh-Ying
authors: YY
authors: Yeh
authors: Leslie
authors: L
authors: Andritsos
authors: Jeffrey A
authors: JA
authors: Jones
authors: Joseph M
authors: JM
authors: Flynn
authors: Kristie A
authors: KA
authors: Blum
authors: Xiaoli
authors: X
authors: Zhang
authors: Amy
authors: A
authors: Lehman
authors: Hui
authors: H
authors: Kong
authors: Metin
authors: M
authors: Gurcan
authors: Michael R
authors: MR
authors: Grever
authors: Amy J
authors: AJ
authors: Johnson
authors: John C
authors: JC
authors: Byrd
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018929:Cell Culture Techniques; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013217:Starvation / Q000473:pathology; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C077990:alvocidib; D018844:Cyclin-Dependent Kinases; D014740:Vidarabine; C024352:fludarabine