Duraj J, Takacsova X, Sedlak J, Sulikova M, Hunakova L, Bies J, Chorvath B
Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 83391 Bratislava, Slovakia.
Anticancer Res. 2000 Nov-Dec;20(6B):4627-32.
The non-immunosuppressive cyclosporine analog PSC 833 has been shown to reverse multidrug-resistance of neoplastic cells including the MDR-1 gene coded P-glycoprotein (P-gp)-mediated cells resistant to paclitaxel.
Apoptosis was demonstrated in drug-sensitive HL-60 and multidrug-resistant human promyelocytic leukemia HL-60/ADR (MRP) and HL-60/VCR (MDR-1) cells in vitro with the aid of flow cytometry, DNA analysis and western blotting.
The techniques used herein determined accumulation of paclitaxel/PSC 833 induced apoptotic cells with sub-G0 (hypodiploid) DNA content and blocked in the G2/M phase of the cell cycle, internucleosomal DNA fragmentation, poly (ADP-ribose) polymerase cleavage, Bcl-2 modulation and Bax up-regulation, without any significant alterations in the levels of Bcl-xL, CD95/Fas or Fas-L proteins.
Drug resistance modulator PSC 833 abolished the P-gp-mediated multidrug-resistance to paclitaxel and paclitaxel-induced apoptosis in human myeloid leukemia (HL-60/VCR) cells in vitro. Furthermore, PSC 833 alone induced apoptosis in parental drug-sensitive leukemia cells, but not in both multidrug-resistant sublines studied.
非免疫抑制性环孢素类似物PSC 833已被证明可逆转肿瘤细胞的多药耐药性，包括由MDR-1基因编码的P-糖蛋白（P-gp）介导的对紫杉醇耐药的细胞。
借助流式细胞术、DNA分析和蛋白质印迹法，在体外对药物敏感的HL-60细胞以及多药耐药的人早幼粒细胞白血病HL-60/ADR（多药耐药相关蛋白）和HL-60/VCR（MDR-1）细胞进行凋亡检测。
本文所采用的技术确定了紫杉醇/PSC 833诱导的凋亡细胞积累，这些细胞具有亚G0（亚二倍体）DNA含量，并停滞在细胞周期的G2/M期，出现核小体间DNA片段化、聚（ADP-核糖）聚合酶裂解、Bcl-2调节以及Bax上调，而Bcl-xL、CD95/Fas或Fas-L蛋白水平无任何显著变化。
耐药调节剂PSC 833消除了P-gp介导的对紫杉醇的多药耐药性以及紫杉醇在体外诱导人髓性白血病（HL-60/VCR）细胞凋亡的作用。此外，PSC 833单独即可诱导亲代药物敏感白血病细胞凋亡，但在所研究的两种多药耐药亚系细胞中则不然。
