Shiraki Nobuaki, Okamura Keiko, Tokunaga Jin, Ohmura Takafumi, Yasuda Kazuto, Kawaguchi Takeo, Hamada Akinobu, Nakano Masahiro
Department of Pharmacy, Kumamoto University Hospital, Kumamoto 860-8556, Japan.
Jpn J Cancer Res. 2002 Feb;93(2):209-15. doi: 10.1111/j.1349-7006.2002.tb01260.x.
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.
抗癌治疗失败的最重要原因之一是多药耐药性（MDR）的产生。表现出MDR现象的肿瘤细胞的主要特征是对具有不同作用机制的结构不相关的细胞毒性药物产生交叉耐药性，以及MDR1基因的过表达，该基因编码一种名为P-糖蛋白（P-gp）的跨膜糖蛋白。本研究评估了D2多巴胺能受体激动剂溴隐亭与不表达P-gp的亚系相比，对表达P-gp的细胞系中抗癌药物细胞毒性和P-gp活性的影响。在使用过表达人P-gp的猪肾上皮LLC-PK1和L-MDR1细胞进行的钙黄绿素-AM外排试验中，环孢素和维拉帕米对P-gp的K(i)值分别为1.09和540 microM，溴隐亭的K(i)值为6.52 microM。10 microM的溴隐亭将K562-DXR中阿霉素（DXR）的IC50从9000降至270 ng/ml，将K562-VCR中长春新碱（VCR）的IC50从700降至0.30 ng/ml，而K562亚系中DXR和VCR的IC50值仅受到这些药物的轻微影响。溴隐亭恢复了DXR、VCR、长春碱、长春瑞滨和依托泊苷对过表达P-gp的MDR肿瘤细胞的抗癌作用。这些观察结果表明，溴隐亭有可能在临床情况下逆转涉及外排蛋白P-gp的肿瘤MDR。
