KBH-A42, a histone deacetylase inhibitor, inhibits the growth of doxorubicin-resistant leukemia cells expressing P-glycoprotein

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Title
KBH-A42, a histone deacetylase inhibitor, inhibits the growth of doxorubicin-resistant leukemia cells expressing P-glycoprotein
Author(s)
Moorim Kang; Kiho Lee; Jong Soon KangChang Woo LeeKi Hoon Lee; Jang Hyun Kim; Jeung Wook Yang; Bo Geum Kim; G Han; J S Kang; Song Kyu Park; Hwan Mook Kim
Bibliographic Citation
Oncology Reports, vol. 23, no. 3, pp. 801-809
Publication Year
2010
Abstract
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-gpnegative K562 human leukemia cells, but did not show substantial inhibition on the growth of P-gp-positive K562/ADR cells even at 10 μM, the highest concentration of KBHA42 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.
Keyword
ApoptosisCaspaseCell cycle arrestHistone deacetylase inhibitorp21 WAF1
ISSN
1021-335X
Publisher
Spandidos Publ Ltd
DOI
http://dx.doi.org/10.3892/or-00000701
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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