Abstract
DNA damage induces apoptosis of cells of hematological origin. Apoptosis is also widely believed to be the major antiproliferative mechanism of DNA damaging anticancer drugs in other cell types, and a large number of laboratories have studied drug-induced acute apoptosis (within 24 hours) of carcinoma cells. It is, however, often overlooked that induction of apoptosis of carcinoma cells generally requires drug concentrations that are at least one order of magnitude higher than those required for loss of clonogenicity. This is true for different DNA damaging drugs such as cisplatin, doxorubicin and camptothecin. We here discuss apoptosis induction by DNA damaging agents using cisplatin as an example. Recent studies have shown that cisplatin induces caspase activation in enucleated cells (cytoplasts lacking a cell nucleus). Cisplatin-induced apoptosis in both cells and cytoplasts is associated with rapid induction of cellular reactive oxygen species and increases in [Ca2+]i. Cisplatin has also been reported to induce clustering of Fas/CD95 in the plasma membrane. Available data suggest that the primary responses to cisplatin-induced DNA damage are induction of longterm growth arrest (“premature cell senescence”) and mitotic catastrophe, whereas acute apoptosis may be due to “offtarget effects” not necessarily involving DNA damage.
Keywords: Cisplatin, JNK activation, Bcl-2, Mitochondrial DNA, apoptosis
Mini-Reviews in Medicinal Chemistry
Title: Mechanisms of Action of DNA-Damaging Anticancer Drugs in Treatment of Carcinomas: Is Acute Apoptosis an “Off-Target” Effect?
Volume: 7 Issue: 10
Author(s): Aleksandra Mandic Havelka, Maria Berndtsson, Maria Hagg Olofsson, Maria C. Shoshan and Stig Linder
Affiliation:
Keywords: Cisplatin, JNK activation, Bcl-2, Mitochondrial DNA, apoptosis
Abstract: DNA damage induces apoptosis of cells of hematological origin. Apoptosis is also widely believed to be the major antiproliferative mechanism of DNA damaging anticancer drugs in other cell types, and a large number of laboratories have studied drug-induced acute apoptosis (within 24 hours) of carcinoma cells. It is, however, often overlooked that induction of apoptosis of carcinoma cells generally requires drug concentrations that are at least one order of magnitude higher than those required for loss of clonogenicity. This is true for different DNA damaging drugs such as cisplatin, doxorubicin and camptothecin. We here discuss apoptosis induction by DNA damaging agents using cisplatin as an example. Recent studies have shown that cisplatin induces caspase activation in enucleated cells (cytoplasts lacking a cell nucleus). Cisplatin-induced apoptosis in both cells and cytoplasts is associated with rapid induction of cellular reactive oxygen species and increases in [Ca2+]i. Cisplatin has also been reported to induce clustering of Fas/CD95 in the plasma membrane. Available data suggest that the primary responses to cisplatin-induced DNA damage are induction of longterm growth arrest (“premature cell senescence”) and mitotic catastrophe, whereas acute apoptosis may be due to “offtarget effects” not necessarily involving DNA damage.
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Cite this article as:
Havelka Mandic Aleksandra, Berndtsson Maria, Olofsson Hagg Maria, Shoshan C. Maria and Linder Stig, Mechanisms of Action of DNA-Damaging Anticancer Drugs in Treatment of Carcinomas: Is Acute Apoptosis an “Off-Target” Effect?, Mini-Reviews in Medicinal Chemistry 2007; 7 (10) . https://dx.doi.org/10.2174/138955707782110196
DOI https://dx.doi.org/10.2174/138955707782110196 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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