Tags

Type your tag names separated by a space and hit enter

Induction of apoptosis by apicidin, a histone deacetylase inhibitor, via the activation of mitochondria-dependent caspase cascades in human Bcr-Abl-positive leukemia cells.
Clin Cancer Res. 2003 Oct 15; 9(13):5018-27.CC

Abstract

PURPOSE

Apicidin, a histone deacetylase inhibitor, is a novel cyclic tetrapeptide that exhibits potent antiproliferative activity against various cancer cell lines. The aim of this study was to examine the potential of apicidin to induce apoptosis in human Bcr-Abl-positive leukemia cells and to assess the mechanism of apicidin-induced apoptosis.

EXPERIMENTAL DESIGN

Cells were exposed to various concentrations of apicidin for 2-72 h, after which the levels of apoptosis, histone acetylation, mitochondrial damage, caspase activation, and Bcr-Abl expression were assessed.

RESULTS

Apicidin induced apoptosis in K562 cells in a concentration- and time-dependent manner. Similarly, apicidin notably induced the apoptosis in the primary leukemic blasts obtained from chronic myelogenous leukemia patients in blast crisis. The acetylated histone H4 levels increased in a concentration-dependent manner in the K562 cells. However, the timing of cell death caused by apicidin did not exactly correlate with the histone deacetylase inhibitory effect. The disruption of the mitochondrial membrane potential, cytochrome c release into the cytosol, and the mitochondrial Bax translocation were notably demonstrated after the apicidin treatment. Apicidin induced the proteolytic cleavage of procaspase-9, -3, -8, and poly(ADP-ribose) polymerase. Pretreatment of the K562 cells with the caspase-3 inhibitor, DEVD-CHO, completely inhibited the apicidin-induced apoptosis, suggesting that apicidin-induced apoptosis was caspase-dependent. The Fas/Fas ligand death receptor pathway was not involved in the apicidin-mediated apoptosis in K562 cells. Pretreatment of the cells with the caspase-9 inhibitor LEHD-fmk abrogated the apicidin- induced cleavage of procaspase-3, -8, and poly(ADP-ribose) polymerase. The p210 Bcr-Abl protein levels were notably decreased after the apicidin treatment, with near complete loss after 48 h. Reverse transcription-PCR assay demonstrated that the Bcr-Abl mRNA level was also remarkably decreased in a time-dependent manner.

CONCLUSIONS

These results indicate that apicidin effectively induces the apoptosis of Bcr-Abl-positive leukemia cells through the activation of the mitochondrial pathway-dependent caspase cascades. The down-regulation of Bcr-Abl mRNA might also be one of the mechanisms implicated in the apicidin-mediated apoptosis in the K562 cells. This study provides the rationale to additionally investigate apicidin as a potential therapeutic agent for the drug-resistant Bcr-Abl-positive leukemia cells.

Authors+Show Affiliations

Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14581377

Citation

Cheong, June-Won, et al. "Induction of Apoptosis By Apicidin, a Histone Deacetylase Inhibitor, Via the Activation of Mitochondria-dependent Caspase Cascades in Human Bcr-Abl-positive Leukemia Cells." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 9, no. 13, 2003, pp. 5018-27.
Cheong JW, Chong SY, Kim JY, et al. Induction of apoptosis by apicidin, a histone deacetylase inhibitor, via the activation of mitochondria-dependent caspase cascades in human Bcr-Abl-positive leukemia cells. Clin Cancer Res. 2003;9(13):5018-27.
Cheong, J. W., Chong, S. Y., Kim, J. Y., Eom, J. I., Jeung, H. K., Maeng, H. Y., Lee, S. T., & Min, Y. H. (2003). Induction of apoptosis by apicidin, a histone deacetylase inhibitor, via the activation of mitochondria-dependent caspase cascades in human Bcr-Abl-positive leukemia cells. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 9(13), 5018-27.
Cheong JW, et al. Induction of Apoptosis By Apicidin, a Histone Deacetylase Inhibitor, Via the Activation of Mitochondria-dependent Caspase Cascades in Human Bcr-Abl-positive Leukemia Cells. Clin Cancer Res. 2003 Oct 15;9(13):5018-27. PubMed PMID: 14581377.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of apoptosis by apicidin, a histone deacetylase inhibitor, via the activation of mitochondria-dependent caspase cascades in human Bcr-Abl-positive leukemia cells. AU - Cheong,June-Won, AU - Chong,So Young, AU - Kim,Ji Yeon, AU - Eom,Ju In, AU - Jeung,Hoi Kyung, AU - Maeng,Ho Young, AU - Lee,Seung Tae, AU - Min,Yoo Hong, PY - 2003/10/29/pubmed PY - 2004/6/21/medline PY - 2003/10/29/entrez SP - 5018 EP - 27 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 9 IS - 13 N2 - PURPOSE: Apicidin, a histone deacetylase inhibitor, is a novel cyclic tetrapeptide that exhibits potent antiproliferative activity against various cancer cell lines. The aim of this study was to examine the potential of apicidin to induce apoptosis in human Bcr-Abl-positive leukemia cells and to assess the mechanism of apicidin-induced apoptosis. EXPERIMENTAL DESIGN: Cells were exposed to various concentrations of apicidin for 2-72 h, after which the levels of apoptosis, histone acetylation, mitochondrial damage, caspase activation, and Bcr-Abl expression were assessed. RESULTS: Apicidin induced apoptosis in K562 cells in a concentration- and time-dependent manner. Similarly, apicidin notably induced the apoptosis in the primary leukemic blasts obtained from chronic myelogenous leukemia patients in blast crisis. The acetylated histone H4 levels increased in a concentration-dependent manner in the K562 cells. However, the timing of cell death caused by apicidin did not exactly correlate with the histone deacetylase inhibitory effect. The disruption of the mitochondrial membrane potential, cytochrome c release into the cytosol, and the mitochondrial Bax translocation were notably demonstrated after the apicidin treatment. Apicidin induced the proteolytic cleavage of procaspase-9, -3, -8, and poly(ADP-ribose) polymerase. Pretreatment of the K562 cells with the caspase-3 inhibitor, DEVD-CHO, completely inhibited the apicidin-induced apoptosis, suggesting that apicidin-induced apoptosis was caspase-dependent. The Fas/Fas ligand death receptor pathway was not involved in the apicidin-mediated apoptosis in K562 cells. Pretreatment of the cells with the caspase-9 inhibitor LEHD-fmk abrogated the apicidin- induced cleavage of procaspase-3, -8, and poly(ADP-ribose) polymerase. The p210 Bcr-Abl protein levels were notably decreased after the apicidin treatment, with near complete loss after 48 h. Reverse transcription-PCR assay demonstrated that the Bcr-Abl mRNA level was also remarkably decreased in a time-dependent manner. CONCLUSIONS: These results indicate that apicidin effectively induces the apoptosis of Bcr-Abl-positive leukemia cells through the activation of the mitochondrial pathway-dependent caspase cascades. The down-regulation of Bcr-Abl mRNA might also be one of the mechanisms implicated in the apicidin-mediated apoptosis in the K562 cells. This study provides the rationale to additionally investigate apicidin as a potential therapeutic agent for the drug-resistant Bcr-Abl-positive leukemia cells. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/14581377/Induction_of_apoptosis_by_apicidin_a_histone_deacetylase_inhibitor_via_the_activation_of_mitochondria_dependent_caspase_cascades_in_human_Bcr_Abl_positive_leukemia_cells_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=14581377 DB - PRIME DP - Unbound Medicine ER -