Document Detail


Distamycin A enhances the cytotoxicity of duocarmycin A and suppresses duocarmycin A-induced apoptosis in human lung carcinoma cells.
MedLine Citation:
PMID:  17321782     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Duocarmycin A (Duo), which is one of well-known antitumor antibiotics, efficiently alkylates adenine N3 at the 3' end of AT-rich sequences in the DNA. The addition of a minor groove binder, distamycin A (Dist), not only accerelates the reactivity of Duo with oligonucleotide duplex but also switches the DNA-alkylation site to guanine in GC-rich sequences. Here we examined cytotoxic effect of Duo in the coexistence of Dist using human lung carcinoma (HLC-2) cells. The cytotoxicity of Duo to HLC-2 cells was enhanced 10 times by the addition of 0.5microg/ml Dist, which was much lower than the IC(50) value of 16microg/ml. Addition of Duo alone to HLC-2 cells resulted in typically apoptotic changes, including chromatin condensation, sub-G1 accumulation in DNA histogram pattern, and decrease in procaspase-3 and 9 levels. Interestingly, these apoptotic characteristics in Duo-treated cells were suppressed by the addition of 0.5microg/ml Dist, and the G2/M population in the cell cycle progression of HLC-2 cells was largely unchanged in the coexistence of Dist along with the extremely low accumulation of p53 and higher induction of p21. In contrast, the treatment of HLC-2 cells with Dist (16microg/ml) alone was observed to induce the accumulation of p53 and cell cycle arrest at the G1 phase. These results indicate that Dist suppresses apoptosis induced by Duo as well as enhances Duo-induced cytotoxicity in living cells, and may contribute to chemotherapy for tumors resistant to inducing apoptotic cell death.
Authors:
Mikako Hirota; Tsuyoshi Fujiwara; Satoru Mineshita; Hiroshi Sugiyama; Hirobumi Teraoka
Publication Detail:
Type:  Journal Article     Date:  2007-01-24
Journal Detail:
Title:  The international journal of biochemistry & cell biology     Volume:  39     ISSN:  1357-2725     ISO Abbreviation:  Int. J. Biochem. Cell Biol.     Publication Date:  2007  
Date Detail:
Created Date:  2007-04-20     Completed Date:  2007-08-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9508482     Medline TA:  Int J Biochem Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  988-96     Citation Subset:  IM    
Affiliation:
Department of Pathological Biochemistry, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-Ku, Tokyo 101-0062, Japan. hs@kuchem.kyoto-u.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Alkylating Agents / pharmacology
Antibiotics, Antineoplastic / pharmacology
Apoptosis / drug effects*
Blotting, Western
Caspase 3 / metabolism
Caspase 9 / metabolism
Cell Cycle / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Distamycins / pharmacology*
Flow Cytometry
Humans
Indoles / pharmacology*
Inhibitory Concentration 50
Lung Neoplasms / genetics,  metabolism,  pathology
Pyrrolidinones / pharmacology
Time Factors
Tumor Suppressor Protein p53 / metabolism
Chemical
Reg. No./Substance:
0/Alkylating Agents; 0/Antibiotics, Antineoplastic; 0/Distamycins; 0/Indoles; 0/Pyrrolidinones; 0/Tumor Suppressor Protein p53; 118292-34-5/duocarmycin A; 636-47-5/stallimycin; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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