Choi S U, Park S H, Kim K H, Choi E J, Kim S, Park W K, Zhang Y H, Kim H S, Jung N P, Lee C O
Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Yusong, Taejon.
Anticancer Drugs. 1998 Mar;9(3):255-61. doi: 10.1097/00001813-199803000-00008.
The occurrence of resistance to chemotherapeutic drugs is a major problem for successful cancer treatment and reducing drug accumulation by P-glycoprotein (P-gp) is one of the major mechanisms of multidrug resistance (MDR). The present study was performed to evaluate the MDR-reversal abilities of two bisbenzylisoquinoline alkaloids, tetrandine (TET) and fangchinoline (FAN), compared with verapamil (VER), a well-known P-gp modulator. TET (3.0 microM), FAN (3.0 microM) and VER (10.0 microM) reduced the paclitaxel (TAX) concentration required to achieve 50% inhibition of cell growth (EC50) to HCT15 (P-gp-positive) cells about 3100-, 1900- and 410-fold, and these compounds also reduced the EC50 value of actinomycin D (AMD) about 36.0-, 45.9- and 18.2-fold in the cells, respectively. Meanwhile, TET, FAN and VER had no effect on the cytotoxicity of the drugs to SK-OV-3 (P-gp-negative) cells. On the other hand, TET (3.0 microM), FAN (3.0 microM) and VER (10.0 microM) similarly enhanced the accumulation rates of rhodamine 123, a well known P-gp substrate, in HCT15 cells (200-250%). After efflux for 2 h with fresh medium, TET and FAN also enhanced the residual rate of rhodamine 123 about 5.0- and 2.6-fold in comparison with control, respectively. TET, FAN and VER could not affect the accumulation and residual rate of rhodamine 123 in SK-OV-3 cells. From the result, we conclude that TET and FAN enhanced the cytotoxicity of MDR-related drugs via modulation of P-gp.
化疗药物耐药性的出现是癌症治疗成功的主要问题，而通过P-糖蛋白（P-gp）减少药物蓄积是多药耐药（MDR）的主要机制之一。本研究旨在评估两种双苄基异喹啉生物碱粉防己碱（TET）和汉防己甲素（FAN）与著名的P-gp调节剂维拉帕米（VER）相比的MDR逆转能力。TET（3.0微摩尔）、FAN（3.0微摩尔）和VER（10.0微摩尔）分别将使HCT15（P-gp阳性）细胞生长抑制50%所需的紫杉醇（TAX）浓度（EC50）降低约3100倍、1900倍和410倍，并且这些化合物还分别将放线菌素D（AMD）的EC50值在细胞中降低约36.0倍、45.9倍和18.2倍。同时，TET、FAN和VER对药物对SK-OV-3（P-gp阴性）细胞的细胞毒性没有影响。另一方面，TET（3.0微摩尔）、FAN（3.0微摩尔）和VER同样增强了著名的P-gp底物罗丹明123在HCT15细胞中的蓄积率（200%-250%）。用新鲜培养基外排2小时后，与对照相比，TET和FAN还分别将罗丹明123的残留率提高了约5.0倍和2.6倍。TET、FAN和VER不影响罗丹明123在SK-OV-3细胞中的蓄积和残留率。根据结果，我们得出结论，TET和FAN通过调节P-gp增强了MDR相关药物的细胞毒性。
