Document Detail


Antitumor 1-nitroacridine derivative C-1748, induces apoptosis, necrosis or senescence in human colon carcinoma HCT8 and HT29 cells.
MedLine Citation:
PMID:  20026080     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
C-1748 is a DNA-binding agent with potent antitumor activity, especially towards prostate and colon carcinoma xenografts in mice. Here, we elucidated the nature of cellular response of human colon carcinoma HCT8 and HT29 cells to C-1748 treatment, at biologically relevant concentrations (EC(90) and their multiplicity). Cell cycle analysis showed gradual increase in HCT8 cells with sub-G1 DNA content (25% after 72h) considered as apoptotic. Hypodiploid cell population increased up to 60% upon treatment with 4x EC(90) concentration of the drug. Compared with HCT8 cells, the fraction of sub-G1 HT29 cells did not exceed 14%, even following 4-fold dose escalation. Morphological changes and biochemical markers such as: phosphatydylserine externalization, apoptotic DNA breaks, mitochondrial dysfunction and caspase activation confirmed the presence of considerable amount of apoptotic HCT8 cells but only a low amount of apoptotic HT29 cells. Next, we demonstrated that HCT8 cells surviving after exposure to C-1748 were in the state of senescence, based on altered cell morphology and expression of a pH 6-dependent beta-galactosidase. On the contrary, no beta-galactosidase staining was observed in HT29 cells after C-1748 treatment. Moreover, prolonged drug incubation (up to 168h) resulted in massive detachment of cells from culture plates, which together with Annexin V/PI results, indicated that necrosis was the main response of HT29 cells to C-1748 treatment. We also determined the ability of C-1748 to induce reactive oxygen species (ROS) in colon cancer cells and demonstrated, that generation of ROS was not essential for C-1748-induced apoptosis and cytotoxic activity of this drug.
Authors:
Ewa Augustin; Anna Mo?-Rompa; Dorota Nowak-Ziatyk; Jerzy Konopa
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-12-21
Journal Detail:
Title:  Biochemical pharmacology     Volume:  79     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-03-08     Completed Date:  2010-04-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1231-41     Citation Subset:  IM    
Copyright Information:
2009 Elsevier Inc. All rights reserved.
Affiliation:
Department of Pharmaceutical Technology and Biochemistry, Gda?sk University of Technology, Chemical Faculty, Narutowicza Str. 11/12, 80-233 Gda?sk, Poland. augustin@chem.pg.gda.pl
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / chemistry,  pharmacology*
Apoptosis / drug effects*
Cell Line, Tumor
Colonic Neoplasms / drug therapy*
Dose-Response Relationship, Drug
Humans
Molecular Structure
Necrosis / chemically induced*
Nitracrine / analogs & derivatives*,  chemistry,  pharmacology
Chemical
Reg. No./Substance:
0/9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine; 0/Antineoplastic Agents; 4533-39-5/Nitracrine

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


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