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Apoptosis and cancer chemotherapy
C M Chresta1, E L Arriola, J A Hickman
1Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, UK.
Abstract:
Cytotoxic drugs currently remain as the basis for the chemotherapy of metastatic cancer. Why they fail to kill sufficient tumour cells in the major human solid cancers, such as the carcinomas, is suggested in this review to be due to the inherent inability of these cells to engage apoptosis after drug-induced damage. As a paradigm for drug resistant cancers, the resistance of bladder carcinoma cell lines to DNA damaging drugs is described here in terms of their response to the topoisomerase II poison etoposide. 60%-70% of bladder carcinomas have mutant p53; this can prevent the detection of and response to DNA damage. In vitro studies with a bladder carcinoma cell line containing a wild type p53 showed that it underwent a G1 checkpoint after etoposide, potentially allowing DNA damage repair, as well as apoptosis. In lines with mutant or non-functional p53 there is no checkpoint and no apoptosis. All lines showed constitutive expression of bcl-2 and bcl-XL (the suppressors of apoptosis) with low and non-inducible levels of bax (a promoter of apoptosis). Taken together, this menu of gene expression is more favourable to survival than apoptosis after the imposition of drug-induced DNA damage and may contribute to their inherent drug resistance.
Insights
Solid tumors like bladder carcinomas resist chemotherapy because their cells cannot undergo apoptosis after drug damage. Mutant p53 and altered gene expression (bcl-2, bcl-XL, bax) favor survival over cell death, contributing to drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cytotoxic chemotherapy is standard for metastatic cancer but often fails in solid tumors.
- Drug resistance in carcinomas may stem from an inability to initiate apoptosis following DNA damage.
Purpose of the Study:
- To investigate the mechanisms of drug resistance in bladder carcinoma cell lines.
- To examine the role of p53 and apoptosis-regulating genes in etoposide resistance.
Main Methods:
- Utilized bladder carcinoma cell lines with varying p53 statuses (wild-type vs. mutant/non-functional).
- Assessed cellular response to the topoisomerase II inhibitor etoposide.
- Analyzed gene expression of apoptosis regulators (bcl-2, bcl-XL, bax).
Main Results:
- Wild-type p53 bladder cancer cells exhibited a G1 checkpoint, allowing DNA repair and apoptosis post-etoposide.
- Mutant or non-functional p53 lines lacked checkpoints and apoptosis.
- All lines displayed constitutive bcl-2/bcl-XL expression and low, non-inducible bax, favoring survival.
Conclusions:
- Bladder carcinomas' inherent drug resistance is linked to impaired apoptosis induction.
- Mutant p53 and skewed expression of apoptosis regulators (bcl-2, bcl-XL, bax) contribute to chemoresistance.
- Targeting these pathways may overcome drug resistance in solid tumors.