Mechanisms of action of DNA-damaging anticancer drugs in treatment of carcinomas: is acute apoptosis an "off-target" effect?
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 [Ca(2+)](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 long-term growth arrest ("premature cell senescence") and mitotic catastrophe, whereas acute apoptosis may be due to "off-target effects" not necessarily involving DNA damage.
Havelka
Aleksandra Mandic
AM
Cancer Canter Karolinska, Department of Oncology and Pathology, Karolinska, Institute and Hospital, S-171 76 Stockholm, Sweden.
Berndtsson
Maria
M
Olofsson
Maria Hägg
MH
Shoshan
Maria C
MC
Linder
Stig
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013997:Time Factors
D000970:Antineoplastic Agents; D002945:Cisplatin