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Cellular drug efflux and reversal therapy of cancer
1Department of Medical Biology, University of Tennessee Medical Center, Knoxville 37920, USA.
Abstract:
A prevalent form of multidrug resistance (MDR) in cancer cells is caused by an ATP-dependent drug efflux pump; this pump catalyzes the rapid exit of cytotoxic chemotherapy drugs from the cells. The Michaelis equation can be used to describe drug efflux through the MDR pump at a low drug substrate concentration [S]. The inhibition mechanism of an MDR reversal agent can be characterized when two different values of [S] are used to determine two values for the half-inhibition of efflux through the pump (I50). The reaction is noncompetitive when the two values of I50 are identical; the reaction is competitive when an increase in [S] produces a significant increase in the value of I50. The I50 has been determined for several different reversal agents with the substrate rhodamine 123. The inhibition potency observed is: cyclosporin A > DMDP > amiodarone > verapamil > quinidine > quinine > propranolol. Chemotherapy drugs that are potent inhibitors of the MDR pump could be used for the treatment of MDR neoplasia.
Insights
Multidrug resistance (MDR) in cancer is often due to drug efflux pumps. This study characterizes MDR reversal agents, finding potent inhibitors that could treat MDR neoplasia.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) in cancer cells frequently involves ATP-dependent drug efflux pumps that expel chemotherapy drugs.
- Understanding these pumps is crucial for developing effective cancer treatments.
Purpose of the Study:
- To characterize the inhibition mechanisms of MDR reversal agents.
- To evaluate the potency of various compounds in reversing MDR.
Main Methods:
- Utilized the Michaelis equation to model drug efflux through MDR pumps at varying substrate concentrations ([S]).
- Determined half-inhibition concentrations (I50) for different reversal agents using rhodamine 123 as a substrate.
- Classified inhibition as competitive or noncompetitive based on I50 values at different [S].
Main Results:
- Established a ranking of inhibition potency for several MDR reversal agents: cyclosporin A > DMDP > amiodarone > verapamil > quinidine > quinine > propranolol.
- Demonstrated that the inhibition mechanism can be competitive or noncompetitive depending on the agent and substrate concentration.
- Identified potent inhibitors of the MDR pump.
Conclusions:
- Potent MDR pump inhibitors, such as cyclosporin A and DMDP, show promise for overcoming drug resistance in cancer.
- These findings suggest a potential therapeutic strategy for treating MDR neoplasia using effective MDR pump inhibitors.