title: Bromocriptine reverses P-glycoprotein-mediated multidrug resistance in tumor cells.
abstract: 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 P-glycoprotein (P-gp). This study evaluated whether bromocriptine, a D2 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 microM, respectively, and that of bromocriptine was 6.52 microM in a calcein-AM efflux assay using porcine kidney epithelial LLC-PK1 and L-MDR1 cells, overexpressing human P-gp. Bromocriptine at 10 microM reduced the IC50 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 IC50 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.
authors.affiliation: Department of Pharmacy, Kumamoto University Hospital, Kumamoto 860-8556, Japan. ahamada@kaiju.medic.kumamoto-u.ac.jp
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shiraki
authors.forename: Keiko
authors.initials: K
authors.lastname: Okamura
authors.forename: Jin
authors.initials: J
authors.lastname: Tokunaga
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ohmura
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yasuda
authors.forename: Takeo
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakano
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology*; D002460:Cell Line; D018491:Dopamine Agonists / Q000494:pharmacology*; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D020112:Rhodamine 123 / Q000378:metabolism; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018491:Dopamine Agonists; D005452:Fluoresceins; C085925:calcein AM; D020112:Rhodamine 123; D001971:Bromocriptine; D004317:Doxorubicin