| Actinomycin D synergistically enhances the efficacy of the BH3 mimetic ABT-737 by downregulating Mcl-1 expression. | |
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MedLine Citation:
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PMID: 20818182 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Many types of cancer cells possess the ability to evade apoptosis, leading to their rapid and uncontrolled proliferation. As major regulators of apoptosis, Bcl-2 proteins serve as emerging targets for novel chemotherapeutic strategies. In this study, we examined the involvement of Bcl-2 proteins in apoptosis induced by the chemotherapeutic agent actinomycin D. A dramatic decrease in anti-apoptotic myeloid leukemia cell differentiation protein (Mcl-1) mRNA and protein expression was detected upon actinomycin D treatment. Further, Mcl-l over-expression caused resistance to cell death upon treatment with actinomycin D, implicating a role for the down-regulation of Mcl-1 in actinomycin D-induced apoptosis. We also explored the therapeutic potential of actinomycin D in combination with ABT-737, an experimental agent that inhibits anti-apoptotic Bcl-2 proteins. Actinomycin D sensitized cells to ABT-737 treatment in a Bak- or Bax-dependent manner. Importantly, low concentrations of actinomycin D and ABT-737 were more effective in inducing cell death in transformed cells than their untransformed counterparts. A synergistic effect of actinomycin D and ABT-737 on cell death was observed in several human tumor cell lines. Like actinomycin D treatment, knocking down Mcl-1 expression greatly sensitized tumor cells to ABT-737, and Mcl-1 over-expression abrogated the cytotoxic effect induced by ABT-737 and actinomycin D. These results suggest that the down-regulation of Mcl-1 by actinomycin D is likely responsible for the observed synergistic effect between the two drugs. Overall, our studies provide compelling evidence that the combination of actinomycin D and ABT-737 may lead to an effective cancer treatment strategy. |
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Authors:
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Kristen E Olberding; Xiaoli Wang; Yanglong Zhu; Jianmin Pan; Shesh N Rai; Chi Li |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-11-01 |
Journal Detail:
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Title: Cancer biology & therapy Volume: 10 ISSN: 1555-8576 ISO Abbreviation: Cancer Biol. Ther. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-12-29 Completed Date: 2011-07-06 Revised Date: 2011-11-21 |
Medline Journal Info:
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Nlm Unique ID: 101137842 Medline TA: Cancer Biol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 918-29 Citation Subset: IM |
Affiliation:
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Molecular Targets Group, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Combined Chemotherapy Protocols
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pharmacology* Apoptosis* Biphenyl Compounds / pharmacology* Carcinoma, Non-Small-Cell Lung / drug therapy, genetics, metabolism, pathology* Cell Line, Tumor Dactinomycin / pharmacology* Down-Regulation / drug effects Drug Synergism Gene Expression Humans Nitrophenols / pharmacology* Pancreatic Neoplasms / drug therapy, genetics, metabolism, pathology* Peptide Fragments Piperazines / pharmacology Polymerase Chain Reaction Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 / genetics* RNA, Messenger / genetics, metabolism Sulfonamides / pharmacology* bcl-2 Homologous Antagonist-Killer Protein / antagonists & inhibitors, metabolism bcl-2-Associated X Protein / antagonists & inhibitors, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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3P20RR018733-07S1/RR/NCRR NIH HHS; CA106599/CA/NCI NIH HHS; K01 CA106599-06/CA/NCI NIH HHS; K01 CA106599-06S1/CA/NCI NIH HHS; P20 RR018733-07/RR/NCRR NIH HHS; P20 RR018733-07S1/RR/NCRR NIH HHS; RR018733/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ABT-737; 0/BAK1 protein, human; 0/BAX protein, human; 0/Bax protein (53-86); 0/Biphenyl Compounds; 0/Nitrophenols; 0/Peptide Fragments; 0/Piperazines; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Messenger; 0/Sulfonamides; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/bcl-2-Associated X Protein; 0/myeloid cell leukemia sequence 1 protein; 50-76-0/Dactinomycin |
| Comments/Corrections | |
Comment In:
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Cancer Biol Ther. 2010 Nov 23;10(9):930-2
[PMID:
20935462
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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