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Avoidance of doxorubicin resistance in osteosarcoma cells using a new quinoline derivative, MS-209
H Takeshita1, K Kusuzaki, Y Tsuji
1Department of Orthopaedic Surgery, Kyoto Prefectural University of Medicine, Japan.
Abstract:
P-glycoprotein (Pgp), a membrane drug efflux pump, is thought to be responsible for the observed drug resistance in osteosarcoma. We have recently developed Pgp-positive, multidrug resistant (MDR) murine osteosarcoma cell lines, which may be suitable models for the study of drug resistance in osteosarcoma. In this study, we investigated the effect of a newly synthesized quinoline compound, MS-209, on the reversal of doxorubicin (DOX) resistance in these cell lines. Three different types of resistance modifying agents (RMAs) as well as MS-209 were studied. These included the calcium channel blocker verapamil, and the immunosuppressive agents cyclosporin A and FK506. The reversal effects of the RMAs on DOX resistance were assessed by the MTT assay. In the absence of RMAs, the MDR osteosarcoma cells were 20-fold more resistant to DOX than the parental cells. When MS-209 was added at a final concentration of 0.1 to 3 microM to the MDR cells, 3-to 74-fold sensitization was observed. A complete reversal (37-fold sensitization) of the resistance was obtained at 1 microM MS-209. This concentration of MS-209 was 3-, 8- and 28-fold more effective than the same concentration of FK506, verapamil and cyclosporin A, respectively. These results indicate that MS-209 may be a more effective RMA, and that DOX resistance in osteosarcoma cells could be reversed by comparatively low doses of MS-209.
Insights
A new quinoline compound, MS-209, effectively reverses multidrug resistance (MDR) in osteosarcoma cells. MS-209 demonstrated superior efficacy compared to other agents in overcoming doxorubicin resistance.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- P-glycoprotein (Pgp) mediated drug efflux is a key mechanism of multidrug resistance (MDR) in osteosarcoma.
- Established Pgp-positive, MDR murine osteosarcoma cell lines serve as valuable models for studying drug resistance.
Purpose of the Study:
- To investigate the efficacy of a novel quinoline compound, MS-209, in reversing doxorubicin (DOX) resistance in MDR osteosarcoma cells.
- To compare the resistance-modifying activity of MS-209 with established agents like verapamil, cyclosporin A, and FK506.
Main Methods:
- Utilized MTT assay to quantify the reversal of DOX resistance in MDR osteosarcoma cells.
- Administered varying concentrations of MS-209 and other resistance modifying agents (RMAs) to assess their impact on DOX sensitivity.
Main Results:
- MDR osteosarcoma cells exhibited 20-fold resistance to DOX without RMAs.
- MS-209 demonstrated dose-dependent sensitization, achieving a 3- to 74-fold increase in DOX sensitivity.
- A complete reversal of resistance (37-fold sensitization) was observed at 1 microM MS-209, outperforming FK506, verapamil, and cyclosporin A.
Conclusions:
- MS-209 is a potent and effective resistance modifying agent for doxorubicin in osteosarcoma.
- The study suggests that MS-209 may be a promising therapeutic agent for overcoming MDR in osteosarcoma, potentially at lower doses than existing RMAs.