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Modulation of expression of multidrug resistance gene (mdr-1) by adriamycin
1Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Abstract:
The acquired resistance to various drugs in cancer is mediated by P-glycoprotein (P-gp) which is encoded by the mdr-1 gene. An increased level of mdr-1/P-gp was demonstrated after chemotherapy administered to treat cancer in humans. To clarify the direct effect of anticancer drugs on mdr-1/P-gp expression, we investigated the change in transport of adriamycin (ADR), and the expression of the mdr-1 gene and P-gp in an ADR-treated, multidrug-resistant leukemic cell line (K562/ADR500). The addition of ADR induced the over-expression of mdr-1/P-gp, which led to a transient decrease in the intracellular accumulation of ADR although the difference was not statistically significant. A maximal effect was observed after 4 h incubation, returning to the baseline level after further incubation for 12-24 h. The phosphorylation of P-gp was inversely correlated with the levels of P-gp. These observations suggest that ADR itself modulates both the expression and function of P-gp. Determination of the optimal schedule for administering adriamycin is essential to achieving the optimal effect in treating cancer.
Insights
Adriamycin (ADR) chemotherapy can increase P-glycoprotein (P-gp) expression in cancer cells, potentially affecting drug resistance. Understanding this interaction is key to optimizing ADR treatment schedules for better cancer therapy outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Acquired resistance to cancer chemotherapy is often mediated by P-glycoprotein (P-gp), encoded by the mdr-1 gene.
- Elevated mdr-1/P-gp levels are observed in cancer patients post-chemotherapy.
- The direct impact of anticancer drugs on mdr-1/P-gp expression requires clarification.
Purpose of the Study:
- To investigate the direct effect of adriamycin (ADR) on mdr-1/P-gp expression and ADR transport.
- To analyze changes in mdr-1 gene expression and P-gp levels in an ADR-resistant leukemic cell line (K562/ADR500) treated with ADR.
Main Methods:
- Treatment of K562/ADR500 cells with adriamycin (ADR).
- Monitoring of ADR intracellular accumulation.
- Assessment of mdr-1 gene and P-gp expression levels.
- Analysis of P-gp phosphorylation.
Main Results:
- ADR treatment induced mdr-1/P-gp over-expression in K562/ADR500 cells.
- A transient decrease in intracellular ADR accumulation was observed, though not statistically significant.
- Maximal effects on P-gp expression occurred at 4 hours, returning to baseline by 12-24 hours.
- P-gp phosphorylation levels were inversely correlated with P-gp expression levels.
Conclusions:
- Adriamycin itself modulates both the expression and function of P-gp.
- The findings highlight the dynamic interplay between ADR and P-gp.
- Optimizing the administration schedule of adriamycin is crucial for maximizing its therapeutic efficacy in cancer treatment.