MDR Modulators

Can we find some modulators to overcome MDR in cancer patients? Verapamil is the first compound found to be able to reverse MDR. Since the discovery of the reversing effects of verapamil, a large number of compounds, named as chemosensitizers or MDR modulators, were found to be able to reverse the MDR phenotype. There were significant regressions of MDR in murine and human xenograft models by co-administering conventional anti-cancer drugs along with the MDR modulators. Unfortunately, many cancer patients relapsed.

Why cancer patients relapse is not very well understood. Whether the relapsed cancer cells develop resistance to the MDR modulators is not clear yet. What are the mechanisms of modulating effects is also not very well illustrated. We have generated several cell lines overexpressing MRP1 by transfecting baby hamster kidney cells with human MRP1 cDNA. All these MRP1-expressing cell lines are MDR cells. However, their sensitivities to the MDR modulator verapamil are different. Most of the cell lines are highly sensitive to verapamil treatment, whereas one of the cell lines is not sensitive to verapamil, implying resistant to the MDR modulator. We have found that verapamil triggers apoptosis of those verapamil-sensitive cells via glutathione extrusion by MRP1.

We shall continue to study the mechanisms of the other MDR modulators in those verapamil-sensitive MDR cells. In addition, highly verapamil-resistant MDR cells were obtained by stepwise increased concentrations of verapamil. These highly verapamil-resistant cells will be utilized as starting materials to study the mechanism of modulator-resistance. Once the factors or proteins associated with MDR modulator-resistance are identified, inhibitors affecting these factors or proteins will be sought. If the new inhibitors are found, they will be utilized along with conventional anti-cancer drugs and existing MDR modulators to treat the verapamil-resistant MDR cells. Thereby this research may provide a new approach to overcome MDR in cancer patients.