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Actinomycin D causes multidrug resistance and differentiation in a human rhabdomyosarcoma cell line
C Melguizo1, J Prados, J E Fernández
1Department of Morphological Sciences, School of Medicine, University of Granada, Spain.
Abstract:
The emergence of drug-resistant tumor cells remains a major problem in cancer chemotherapy. Resistance to multiple unrelated antineoplastic drugs may be related, in part, to expression of the P-glycoprotein. The cell line RD, derived from an embryonic rhabdomyosarcoma tumor, was used as an in vitro model to examine the development of drug resistance. A cell line resistant to actinomycin D (RD-DAC) was developed by growing RD in increasing concentrations of the drug. The ID50 (concentration of drug needed to induce a 50% reduction in cell growth) of the resultant line to actinomycin D was more than 15 times that of the parental line. The resistant line was cross-resistant to vincristine and doxorubicin. Resistance to actinomycin D resulted in increased P-glycoprotein expression, which was associated with a change in desmin and vimentin expression. These results suggest that exposure to chemotherapeutic drugs can induce not only classical multidrug resistance, but also a process of cellular differentiation in rhabdomyosarcoma cells.
Insights
Chemotherapy resistance in rhabdomyosarcoma cells can increase P-glycoprotein expression, leading to multidrug resistance. This study shows drug exposure may also trigger cellular differentiation in these cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Drug-resistant tumor cells pose a significant challenge in cancer chemotherapy.
- P-glycoprotein expression is implicated in resistance to multiple antineoplastic drugs.
Purpose of the Study:
- To investigate the development of drug resistance in a rhabdomyosarcoma cell line (RD).
- To examine the relationship between drug resistance, P-glycoprotein expression, and cellular differentiation.
Main Methods:
- Development of an actinomycin D-resistant cell line (RD-DAC) from the parental RD line through stepwise drug exposure.
- Assessment of drug resistance by determining the ID50 values for actinomycin D, vincristine, and doxorubicin.
- Analysis of P-glycoprotein, desmin, and vimentin expression in parental and resistant cell lines.
Main Results:
- The RD-DAC cell line exhibited over 15-fold resistance to actinomycin D compared to the parental RD line.
- Cross-resistance to vincristine and doxorubicin was observed in the RD-DAC line.
- Increased P-glycoprotein expression correlated with changes in desmin and vimentin expression in the resistant cells.
Conclusions:
- Chemotherapeutic drug exposure can induce multidrug resistance via P-glycoprotein upregulation in rhabdomyosarcoma.
- Drug treatment may also initiate a process of cellular differentiation in rhabdomyosarcoma cells, alongside resistance development.