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Article: Induction of apoptosis in K562 cells by dicyclohexylammonium salt of hyperforin through a mitochondrial-related pathway
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TitleInduction of apoptosis in K562 cells by dicyclohexylammonium salt of hyperforin through a mitochondrial-related pathway
 
AuthorsLiu, JY2
Liu, Z3
Wang, DM2
Li, MM3
Wang, SX3
Wang, R3
Chen, JP1
Wang, YF3
Yang, DP2
 
KeywordsAntitumor activity
Apoptosis
Hyperforin derivatives
K562 cells
 
Issue Date2011
 
PublisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/chembioint
 
CitationChemico-Biological Interactions, 2011, v. 190 n. 2-3, p. 91-101 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.cbi.2011.02.026
 
AbstractHyperforin is an abundant phloroglucinol-type constituent isolated from the extract of the flowering upper portion of the plant Hypericum perforatum L. The dicyclohexylammonium salt of hyperforin (DCHA-HF) has exhibited antitumor and antiangiogenic activities in various cancer cells. Here, the antitumor effects of DCHA-HF on the chronic myeloid leukemia K562 cell line were investigated for the first time. DCHA-HF exhibited dose- and time-dependent inhibitory activities against K562 cells, with IC 50 values of 8.6 and 3.2 μM for 48 h and 72 h of treatment, respectively, which was more effective than that of the hyperforin. In contrast, little cytotoxic activity was observed with DCHA-HF on HUVECs. DCHA-HF treatment resulted in induction of apoptosis as evidenced from DNA fragmentation, nuclear condensation and increase of early apoptotic cells by DAPI staining analysis, TUNEL assay and Annexin V-FITC/PI double-labeled staining analysis, respectively. Moreover, DCHA-HF elicited dissipation of mitochondrial transmembrane potential that commenced with the release of cytochrome c through down-regulation of expression of anti-apoptotic proteins and up-regulation of expression of pro-apoptotic proteins. DCHA-HF treatment induced activation of the caspase 3, 8, and 9 cascade and subsequent PARP cleavage, and DCHA-HF-induced apoptosis was significantly inhibited by caspase inhibitors. Treated cells were arrested at the G1 phase of the cell cycle and the expression of p53 and p27 Kip1, two key regulators related to cell cycle and apoptosis, was up-regulated. These results suggest that DCHA-HF inhibits K562 cell growth by inducing caspase-dependent apoptosis mediated by a mitochondrial pathway and arresting the cell cycle at the G1 phase. Therefore, DCHA-HF is a potential chemotherapeutic antitumor drug for chronic myeloid leukemia therapy. © 2011 Elsevier Ireland Ltd. All rights reserved.
 
ISSN0009-2797
2012 Impact Factor: 2.967
2012 SCImago Journal Rankings: 0.934
 
DOIhttp://dx.doi.org/10.1016/j.cbi.2011.02.026
 
ISI Accession Number IDWOS:000291119800004
Funding AgencyGrant Number
International Science & Technology Cooperation Program of China2009DFA31230
International Science & Technology Cooperation Program of Guangdong Province, China20090501
National Natural Science Foundation of China81001449
Fundamental Research Funds for the Central Universities21609303
Funding Information:

This work was supported by grants from the International Science & Technology Cooperation Program of China (2009DFA31230), the International Science & Technology Cooperation Program of Guangdong Province, China (20090501), the National Natural Science Foundation of China (81001449), and the Fundamental Research Funds for the Central Universities (21609303).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorLiu, JY
 
dc.contributor.authorLiu, Z
 
dc.contributor.authorWang, DM
 
dc.contributor.authorLi, MM
 
dc.contributor.authorWang, SX
 
dc.contributor.authorWang, R
 
dc.contributor.authorChen, JP
 
dc.contributor.authorWang, YF
 
dc.contributor.authorYang, DP
 
dc.date.accessioned2011-08-26T14:41:02Z
 
dc.date.available2011-08-26T14:41:02Z
 
dc.date.issued2011
 
dc.description.abstractHyperforin is an abundant phloroglucinol-type constituent isolated from the extract of the flowering upper portion of the plant Hypericum perforatum L. The dicyclohexylammonium salt of hyperforin (DCHA-HF) has exhibited antitumor and antiangiogenic activities in various cancer cells. Here, the antitumor effects of DCHA-HF on the chronic myeloid leukemia K562 cell line were investigated for the first time. DCHA-HF exhibited dose- and time-dependent inhibitory activities against K562 cells, with IC 50 values of 8.6 and 3.2 μM for 48 h and 72 h of treatment, respectively, which was more effective than that of the hyperforin. In contrast, little cytotoxic activity was observed with DCHA-HF on HUVECs. DCHA-HF treatment resulted in induction of apoptosis as evidenced from DNA fragmentation, nuclear condensation and increase of early apoptotic cells by DAPI staining analysis, TUNEL assay and Annexin V-FITC/PI double-labeled staining analysis, respectively. Moreover, DCHA-HF elicited dissipation of mitochondrial transmembrane potential that commenced with the release of cytochrome c through down-regulation of expression of anti-apoptotic proteins and up-regulation of expression of pro-apoptotic proteins. DCHA-HF treatment induced activation of the caspase 3, 8, and 9 cascade and subsequent PARP cleavage, and DCHA-HF-induced apoptosis was significantly inhibited by caspase inhibitors. Treated cells were arrested at the G1 phase of the cell cycle and the expression of p53 and p27 Kip1, two key regulators related to cell cycle and apoptosis, was up-regulated. These results suggest that DCHA-HF inhibits K562 cell growth by inducing caspase-dependent apoptosis mediated by a mitochondrial pathway and arresting the cell cycle at the G1 phase. Therefore, DCHA-HF is a potential chemotherapeutic antitumor drug for chronic myeloid leukemia therapy. © 2011 Elsevier Ireland Ltd. All rights reserved.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationChemico-Biological Interactions, 2011, v. 190 n. 2-3, p. 91-101 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.cbi.2011.02.026
 
dc.identifier.citeulike8960873
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.cbi.2011.02.026
 
dc.identifier.epage101
 
dc.identifier.hkuros189749
 
dc.identifier.isiWOS:000291119800004
Funding AgencyGrant Number
International Science & Technology Cooperation Program of China2009DFA31230
International Science & Technology Cooperation Program of Guangdong Province, China20090501
National Natural Science Foundation of China81001449
Fundamental Research Funds for the Central Universities21609303
Funding Information:

This work was supported by grants from the International Science & Technology Cooperation Program of China (2009DFA31230), the International Science & Technology Cooperation Program of Guangdong Province, China (20090501), the National Natural Science Foundation of China (81001449), and the Fundamental Research Funds for the Central Universities (21609303).

 
dc.identifier.issn0009-2797
2012 Impact Factor: 2.967
2012 SCImago Journal Rankings: 0.934
 
dc.identifier.issue2-3
 
dc.identifier.pmid21376709
 
dc.identifier.scopuseid_2-s2.0-79955474334
 
dc.identifier.spage91
 
dc.identifier.urihttp://hdl.handle.net/10722/138120
 
dc.identifier.volume190
 
dc.languageeng
 
dc.publisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/chembioint
 
dc.publisher.placeIreland
 
dc.relation.ispartofChemico-Biological Interactions
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAntineoplastic Agents - chemistry - toxicity
 
dc.subject.meshApoptosis
 
dc.subject.meshHypericum - chemistry
 
dc.subject.meshMitochondria - drug effects - metabolism
 
dc.subject.meshTerpenes - chemistry - toxicity
 
dc.subjectAntitumor activity
 
dc.subjectApoptosis
 
dc.subjectHyperforin derivatives
 
dc.subjectK562 cells
 
dc.titleInduction of apoptosis in K562 cells by dicyclohexylammonium salt of hyperforin through a mitochondrial-related pathway
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. Sun Yat-Sen University
  3. Jinan University