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

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

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)801-809
Number of pages9
JournalOncology reports
Volume23
Issue number3
DOIs
Publication statusPublished - 2010 Mar

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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