| N,N-Dimethyl phytosphingosine sensitizes HL-60/MX2, a multidrug-resistant variant of HL-60 cells, to doxorubicin-induced cytotoxicity through ROS-mediated release of cytochrome c and AIF. | |
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MedLine Citation:
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PMID: 20512627 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Doxorubicin (Dox) is widely used to treat a variety of tumors. However, resistance to this drug is common, making successful treatment more difficult. Previously, we introduced a novel phytosphingosine derivative, N,N-dimethyl phytosphingosine (DMPS), as a potent anticancer therapeutic agent in human leukemia cells. This study was performed to investigate whether DMPS can sensitize HL-60/MX2, a multidrug-resistant variant of HL-60, to Dox-induced apoptosis. Low concentrations of DMPS sensitized HL-60/MX2 cells to Dox-induced apoptosis. Combined Dox + DMPS treatment-induced apoptosis was accompanied by the activation of caspase-8 and caspase-3 as well as PARP cleavage. Cytochrome c and AIF release were also observed in Dox + DMPS-treated HL60/MX2 cells. Pretreatment with z-VAD-fmk markedly prevented caspase-3 activation and moderately suppressed apoptosis, suggesting that Dox + DMPS-induced apoptosis is somewhat (not completely) dependent on caspase. Cytochrome c and AIF release were not affected by pretreatment with z-VAD-fmk. The ROS scavenger NAC efficiently suppressed not only ROS generation, but also caspase-3-mediated PARP cleavage, apoptosis, and release of cytochrome c and AIF, indicating a role of ROS in combined Dox + DMPS treatment-induced apoptotic death signaling. Taken together, these observations suggest that DMPS may be used as a therapeutic agent for overcoming drug-resistance in cancer cells by enhancing drug-induced apoptosis. |
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Authors:
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Byeong Mo Kim; Yun Jung Choi; Yong Heon Lee; Young Ae Joe; Sung Hee Hong |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Apoptosis : an international journal on programmed cell death Volume: 15 ISSN: 1573-675X ISO Abbreviation: Apoptosis Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-07-15 Completed Date: 2010-10-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9712129 Medline TA: Apoptosis Country: United States |
Other Details:
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Languages: eng Pagination: 982-93 Citation Subset: IM |
Affiliation:
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Korea Institute of Radiological and Medical Sciences, Nowon-Gu, Seoul, Republic of Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylcysteine
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pharmacology Amino Acid Chloromethyl Ketones / metabolism Antibiotics, Antineoplastic / pharmacology Antioxidants / pharmacology Apoptosis Inducing Factor / metabolism* Caspases / antagonists & inhibitors, metabolism Cell Survival Cysteine Proteinase Inhibitors / metabolism Cytochromes c / metabolism* Doxorubicin / pharmacology* Drug Resistance, Multiple / drug effects* Enzyme Activation Free Radical Scavengers / pharmacology HL-60 Cells / drug effects* Humans Mitochondria / metabolism Reactive Oxygen Species / metabolism* Sphingosine / analogs & derivatives*, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Amino Acid Chloromethyl Ketones; 0/Antibiotics, Antineoplastic; 0/Antioxidants; 0/Apoptosis Inducing Factor; 0/Cysteine Proteinase Inhibitors; 0/Free Radical Scavengers; 0/Reactive Oxygen Species; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; 123-78-4/Sphingosine; 23214-92-8/Doxorubicin; 554-62-1/phytosphingosine; 616-91-1/Acetylcysteine; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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