One of the most important causes of anticancer treatment failure is the development of multidrug resistance (MDR). The main characteristics of tumor cells displaying the MDR phenomena are cross-resistance to structurally unrelated cytotoxic drugs having different mechanisms of action and the overexpression of the MDR1 gene, which encodes a transmembrane glycoprotein named Pglycoprotein (P-gp). This study evaluated whether bromocriptine, a D 2 dopaminergic receptor agonist, influenced anticancer drug cytotoxicity and P-gp activity in a P-gp-expressing cell line compared to a non-expressing subline. The K i values for P-gp of cyclosporine and verapamil were 1.09 and 540 µ µ µ µM, respectively, and that of bromocriptine was 6.52 µ µ µ µM in a calcein-AM efflux assay using porcine kidney epithelial LLC-PK1 and L-MDR1 cells, overexpressing human P-gp. Bromocriptine at 10 µ µ µ µM reduced the IC 50 of doxorubicin (DXR) in K562-DXR from 9000 to 270 ng/ml and that of vincristine (VCR) in K562-VCR from 700 to 0.30 ng/ml, whereas the IC 50 values of DXR and VCR in the K562 subline were only marginally affected by these drugs. Bromocriptine restored the anticancer effect of DXR, VCR, vinblastine, vinorelbine and etoposide on MDR-tumor cells overexpressing P-gp. These observations suggest that bromocriptine has the potential to reverse tumor MDR involving the efflux protein P-gp in the clinical situation.
Key words: P-Glycoprotein -Bromocriptine -Multidrug resistanceOne of the most important causes of anticancer treatment failure is the development of multidrug resistance (MDR) in the body. The main characteristics of tumor cells displaying the MDR phenomena are cross-resistance to structurally unrelated cytotoxic drugs having different mechanisms of action and the overexpression of the mdr-1 gene, mapping to chromosome 7 (q21-31), which encodes a transmembrane glycoprotein named P-glycoprotein (Pgp).1-3) P-gp, which is a 170-to 180-kDa membrane glycoprotein, has been extensively investigated with regard to the MDR phenomenon in tumor cells. 4,5) The sequence and domain organization of P-gp are characteristic of the ABC (ATP-binding cassette) superfamily of active transporters, which include the related MDR associated protein (MRP).6) P-gp functions as an ATP-dependent drug-efflux pump, actively excreting a variety of structurally unrelated anticancer drugs, such as anthracyclines, vinca alkaloids, epipodophyllotoxin, actinomycin D, mitomycin C and taxol, from cells before the drugs can exert their cytotoxic effects, thus producing resistance. 7,8) In contrast, MDR modulators, substrates capable of blocking P-gp-mediated drug efflux, have been suggested to reverse P-gp-mediated drug resistance, and to improve the outcome of cancer chemotherapy. MDR modulators include the antiarrhythmic verapamil and the immunosuppressant cyclosporine, and PSC 833 and MS 209 have been developed as second-generation MDR modulators. However, clinical application of these drugs is limited by side-effects and the possibility that they may inhibi...