Document Detail


KBH-A42, a histone deacetylase inhibitor, inhibits the growth of doxorubicin-resistant leukemia cells expressing P-glycoprotein.
MedLine Citation:
PMID:  20127023     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Multidrug resistance mediated by the drug efflux protein, P-glycoprotein (P-gp), is one of the principal mechanisms by which tumor cells escape the cell death induced by chemotherapeutic agents. In our previous study, we demonstrated that KBH-A42 [N-hydroxy-3-(2-oxo-1-(3-phenylpropyl)-1,2,5,6-tetrahydropyridin-3-yl)propanamide], a synthetic histone deacetylase inhibitor, effectively inhibited the growth of several human cancer cell lines. In this study, we attempted to determine whether KBH-A42 was also capable of inhibiting the growth of multidrug-resistant cells. Doxorubicin dose-dependently inhibited the growth of P-gp-negative K562 human leukemia cells, but did not show substantial inhibition on the growth of P-gp-positive K562/ADR cells even at 10 microM, the highest concentration of KBH-A42 used, which increased the acetylation of histones in these leukemia cells, dose-dependently and effectively inhibited the cell growth, regardless of the presence of P-gp in the cells. KBH-A42 mediated G0/G1 cell cycle arrest, probably as the result of the down-regulation of CDK2, CDK4 and CDK6 and the up-regulation of p21WAF1. When the expression of p21WAF1 was ablated by a specific siRNA, the inhibition of cell growth by KBH-A42 was partly reduced in both cell lines. In addition to the cell cycle arrest, KBH-A42 also induced apoptosis in these cells, which was accompanied by the activation of caspases, including caspase-9, caspase-8 and caspase-3. The pan-caspase inhibitor, Z-VAD-fmk, partially blocked the cell death induced by KBH-A42. These results indicate that KBH-A42 induces cell cycle arrest and apoptosis via the up-regulation of p21WAF1 and caspase activation, respectively, regardless of the presence of P-gp in the leukemia cells.
Authors:
Moo Rim Kang; Kiho Lee; Jong Soon Kang; Chang Woo Lee; Ki Hoon Lee; Jang Hyun Kim; Jeong Wook Yang; Bo Geun Kim; Gyoonhee Han; Jong Seong Kang; Song-Kyu Park; Hwan Mook Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncology reports     Volume:  23     ISSN:  1791-2431     ISO Abbreviation:  Oncol. Rep.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-02-03     Completed Date:  2010-04-29     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9422756     Medline TA:  Oncol Rep     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  801-9     Citation Subset:  IM    
Affiliation:
Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Korea.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Caspases / metabolism
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
Doxorubicin / pharmacology*
Drug Resistance, Neoplasm
G0 Phase / drug effects
G1 Phase / drug effects
Histone Deacetylase Inhibitors / pharmacology*
Humans
Hydroxamic Acids / pharmacology*
K562 Cells
P-Glycoprotein / analysis,  physiology*
Piperidones / pharmacology*
Chemical
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/KBH A42; 0/P-Glycoprotein; 0/Piperidones; 23214-92-8/Doxorubicin; EC 3.4.22.-/Caspases

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