Apoptosis induced by anticancer drugs
1CRC Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, UK.
Abstract:
Most of the cytotoxic anticancer drugs in current use have been shown to induce apoptosis in susceptible cells. The fact that disparate agents, which interact with different targets, induce cell death with some common features (endonucleolytic cleavage of DNA, changes in chromatin condensation) suggests that cytotoxicity is determined by the ability of the cell to engage this so-called 'programmed' cell death. The mechanism of the coupling of a stimulus (drug-target interaction) to a response (cell death) is not known, but modulation of this coupling may affect the outcome of drug treatment. This review surveys the recent evidence which supports the idea that the drug-target interaction per se is not the sole determinant of cellular sensitivity of cytotoxic drugs. Studies of the signals which might engage apoptosis, the genes which modulate it and the biochemical process of drug-induced apoptosis itself are described, where possible, for glucocorticoids, topoisomerase inhibitors, alkylating agents, antimetabolites and antihormones. It is suggested that identification of the gene products which couple the stimulus to the response, and so determine intrinsic cellular sensitivity (and resistance), will be important targets for new types of drugs. These might then allow responses to occur in the major cancers of man, which are chemoresistant.
Insights
Cytotoxic anticancer drugs trigger programmed cell death (apoptosis) through common cellular mechanisms, not just drug-target interactions. Understanding these pathways is key to overcoming chemoresistance in cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Most current cytotoxic anticancer drugs induce apoptosis in susceptible cells.
- Common features of drug-induced cell death suggest a role for 'programmed' cell death pathways.
- The precise mechanism linking drug-target interaction to cellular response remains unclear.
Purpose of the Study:
- To review evidence suggesting drug-target interaction is not the sole determinant of cytotoxic drug sensitivity.
- To explore the signals, genes, and biochemical processes involved in drug-induced apoptosis.
- To identify potential new drug targets for overcoming chemoresistance.
Main Methods:
- Literature review of recent evidence on drug-induced apoptosis.
- Analysis of studies on signaling pathways, gene modulation, and biochemical processes.
- Examination of drug classes including glucocorticoids, topoisomerase inhibitors, alkylating agents, antimetabolites, and antihormones.
Main Results:
- Evidence supports that cellular sensitivity to cytotoxic drugs depends on the cell's ability to engage apoptosis.
- The coupling mechanism between drug-target interaction and cell death response is crucial.
- Specific drug classes (glucocorticoids, etc.) engage apoptosis through distinct but related pathways.
Conclusions:
- Drug-target interaction alone does not determine cellular sensitivity to cytotoxic drugs.
- Identifying gene products that couple stimulus to response is critical for understanding sensitivity and resistance.
- New therapeutic strategies targeting these coupling mechanisms could overcome chemoresistance in major human cancers.
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