Chemotherapy resistance is a major obstacle in the treatment of various cancers. Generally, cancer patients refractory to chemotherapy are resistant to multiple anti-tumor drugs. An in vitro (i.e., outside of the living organism) experimental model in cells termed multidrug resistance (MDR), is often due to drug extrusion mechanisms (meaning that drugs that enter the cell are transported back out, and thus are prevented from exerting their effect on the cell). One such drug extrusion mechanism is mediated by overexpression of the P-glycoprotein (P-gp; the human version of the protein encoded by the MDR1 gene), a drug-transporter glycoprotein associated with the cell or plasma membrane (which encloses the cell’s cytoplasm) with a wide variety of drug substrates. Cells that overexpress the MDR1 gene are, hence, resistant to many drugs.
In a study led by Luca Cucullo and Damir Janigro from the Cleveland Clinic Lerner College of Medicine in Ohio that was recently published by the open access journal, BioMed Central, tumor cells that overexpress the MDR1 gene product were shown to lose their resistance to anti-tumor drugs by electrical stimulation. In vitro rodent and human tumor cells refractory to anti-tumor drugs were exposed to continuous, very low intensity (7.5 mA [microamps]) 50 Hertz AC (alternating current) pulses, with ten-second intervals, for a three day period. After electrical stimulation, parallel cultures of cells were treated with increasing concentrations of the chemotherapeutic drug doxorubicin, or with various controls, for three hours, following which cell viability was assessed. The researchers discovered that the cells became sensitive to the anti-cancer drug doxorubicin. The researchers concluded that treatment of the drug-resistant tumor cells with low frequency, low intensity AC stimulation in vitro drastically enhances chemotherapeutic efficacy of doxorubicin, a substrate for the MDR1 glycoprotein drug transporter.
Further investigation demonstrated that electrical stimulation not only decreases levels of the MDR1 glycoprotein transporter, but also changes the localization of the MDR1 glycoprotein from close to the plasma membrane to the cytosol (the fluid portion of the cytoplasm). This altered expression of the MDR1 glycoprotein is believed to have caused the loss of the cell’s drug extrusion ability, which it mediates. Unable to extrude the drug, the cells succumbed to its effect, essentially acquiring sensitivity to the drug, and were killed.
A fuller understanding of the way electrical pulses affect drug-resistant tumors will require further research. However, this technique may be exploited as part of new cancer treatment protocols, such as coupling electrical stimulation with chemotherapy to treat tumors otherwise refractory to drugs, as well as possibly enabling reduction in the amount of chemotheraputic medication used, and thereby in unpleasant side-effects.
