Different DNA lesions trigger distinct cell death responses in HCT116 colon carcinoma cells.

Abstract

The pleiotrophic cellular response to DNA damage includes activation of cell cycle checkpoints, induction of DNA repair pathways, and initiation of programmed cell death among others. The fate of cells with damaged DNA depends on the coordination of these different responses. The clinical efficacy of genotoxic therapies is influenced by cell fate and thus by how the DNA damage response is coordinated. While a great deal has been learned about how different DNA lesions activate distinct cell cycle checkpoints and DNA repair pathways, less is known about whether the type of DNA lesion influences the qualitative and quantitative nature of the cell death response. To address this question, HCT116 colon carcinoma cells have been treated with equally cytotoxic doses of the antitumor DNA alkylating agents adozelesin or bizelesin or the DNA strand scission agent C-1027. The relative contribution of cell cycle arrest and cell death to measured cytotoxicity varied among the three drugs. Apoptotic cell death accounts for most C-1027 cytotoxicity while cell cycle arrest and cell death both contribute to the cytotoxicity of the alkylating agents. Each of the drugs induces a distinct but overlapping pattern of caspase activation. In addition, the cell death response to these drugs is differentially dependent on p53 and p21. These observations suggest that the type of DNA lesion influences not only the relative extent of apoptotic cell death at a given cytotoxic dose but also the qualitative nature of that response.

• Authors: Shaochun Bai, David W Goodrich
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 3 Issue 5 Pg. 613-9 (May 2004) ISSN: 1535-7163 [Print] United States
• PMID: 15141019 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Aminoglycosides
• Antibiotics, Antineoplastic
• Antineoplastic Agents, Alkylating
• Benzofurans
• Cyclohexanecarboxylic Acids
• Cyclohexenes
• Duocarmycins
• Enediynes
• Indoles
• C 1027
• adozelesin
• Urea
• bizelesin

Topics

• Aminoglycosides (pharmacology)
• Antibiotics, Antineoplastic (pharmacology)
• Antineoplastic Agents, Alkylating (pharmacology)
• Benzofurans
• Cell Cycle (drug effects)
• Cell Death (drug effects, physiology)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (pathology)
• Cyclohexanecarboxylic Acids (pharmacology)
• Cyclohexenes
• DNA Damage (drug effects, physiology)
• Dose-Response Relationship, Drug
• Duocarmycins
• Enediynes
• HCT116 Cells
• Humans
• Indoles (pharmacology)
• Inhibitory Concentration 50
• Urea (analogs & derivatives, pharmacology)