Document Detail

Actinomycin D synergistically enhances the efficacy of the BH3 mimetic ABT-737 by downregulating Mcl-1 expression.
MedLine Citation:
PMID:  20818182     Owner:  NLM     Status:  MEDLINE    
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.
Kristen E Olberding; Xiaoli Wang; Yanglong Zhu; Jianmin Pan; Shesh N Rai; Chi Li
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-11-01
Journal Detail:
Title:  Cancer biology & therapy     Volume:  10     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-12-29     Completed Date:  2011-07-06     Revised Date:  2014-06-10    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  918-29     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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
Myeloid Cell Leukemia Sequence 1 Protein
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
3P20RR018733-07S1/RR/NCRR NIH HHS; CA106599/CA/NCI NIH HHS; K01 CA106599/CA/NCI NIH HHS; K01 CA106599-06/CA/NCI NIH HHS; K01 CA106599-06S1/CA/NCI NIH HHS; P20 RR018733/RR/NCRR NIH HHS; P20 RR018733-07/RR/NCRR NIH HHS; P20 RR018733-07S1/RR/NCRR NIH HHS; RR018733/RR/NCRR NIH HHS
Reg. No./Substance:
0/ABT-737; 0/BAK1 protein, human; 0/BAX protein, human; 0/Bax protein (53-86); 0/Biphenyl Compounds; 0/Myeloid Cell Leukemia Sequence 1 Protein; 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; 1CC1JFE158/Dactinomycin
Comment In:
Cancer Biol Ther. 2010 Nov 1;10(9):930-2   [PMID:  20935462 ]

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