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Drug resistance does not correlate with resistance to Fas-mediated apoptosis
K V Cullen1, R A Davey, M W Davey
1Department of Cell and Molecular Biology, University of Technology, Sydney, Westbourne Street, Gore Hill, Sydney, NSW 2065, Australia.
Abstract:
Recent reports have correlated multidrug resistance (MDR) and P-glycoprotein expression with decreased Fas expression and resistance to Fas-mediated apoptosis. We report the MRP-overexpressing MDR subline CEM/E1000 has the same Fas expression (MFI 74.3 +/- 0.7) as the parental CCRF-CEM T-cell leukaemia cells (MFI 70.0 +/- 3.6; P>0.05), and that the level of apoptosis induced by anti-Fas antibody or drug was similar in both cell lines. Further the P-glycoprotein-expressing CEM/VLB(100) subline of the CCRF-CEM cells showed increased Fas expression (MFI 114.8 +/- 3.6; P<0.001) and no resistance to Fas-mediated apoptosis. This questions the hypothesis that selection of drug resistance results in resistance to Fas-mediated apoptosis, with important implications for the rational use of immunotherapy in the treatment of drug resistant cancer.
Insights
Multidrug resistance (MDR) does not necessarily lead to resistance to Fas-mediated apoptosis. This study found no correlation between MDR and reduced Fas expression, challenging existing hypotheses and impacting cancer immunotherapy strategies.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Recent studies suggest a link between multidrug resistance (MDR), P-glycoprotein expression, decreased Fas expression, and resistance to Fas-mediated apoptosis.
- This correlation has significant implications for cancer treatment, particularly immunotherapy.
Purpose of the Study:
- To investigate the relationship between multidrug resistance (MDR) and Fas expression in cancer cell lines.
- To determine if MDR confers resistance to Fas-mediated apoptosis.
- To re-evaluate the hypothesis linking drug resistance to impaired apoptosis pathways.
Main Methods:
- Comparison of Fas expression levels in parental T-cell leukemia cells (CCRF-CEM) and their multidrug-resistant sublines (CEM/E1000 and CEM/VLB(100)).
- Assessment of apoptosis induction by anti-Fas antibody and drugs in these cell lines.
- Flow cytometry was used to quantify Fas expression (Mean Fluorescence Intensity - MFI).
Main Results:
- The MRP-overexpressing MDR subline (CEM/E1000) showed similar Fas expression to parental cells (MFI 74.3 vs 70.0) and comparable sensitivity to Fas-mediated apoptosis.
- The P-glycoprotein-expressing subline (CEM/VLB(100)) exhibited increased Fas expression (MFI 114.8) and no resistance to Fas-mediated apoptosis.
- These findings contradict the proposed correlation between MDR and reduced Fas-mediated apoptosis.
Conclusions:
- The selection for multidrug resistance does not consistently result in resistance to Fas-mediated apoptosis.
- The hypothesis that MDR leads to impaired Fas-mediated apoptosis is questioned.
- These results have critical implications for the strategic use of immunotherapy in treating drug-resistant cancers.