洛匹那韦对LLC/cMOAT细胞的多药耐药逆转机制的研究
摘要
目的:
探讨洛匹那韦对多药耐药LLC/cMOAT细胞的耐药逆转及可能机制
方法:
应用MTT法分析LLC/ CMV和LLC/ cMOAT细胞株对化疗药物的敏感性;采用MTT法对不同浓度的洛匹那韦对细胞株LLC/ CMV和LLC/ cMOAT处理后,观察细胞的生存状态,并确定其非细胞毒性浓度。并同时用MTT法分别检测阿霉素(ADM)长春新碱(VCR )、环磷酰胺(CTX)、顺铂(DDP)处理上述细胞株后半数抑制浓度( IC50 )。再应用流式细胞术检测加入洛匹那韦后细胞内的化疗药物阿霉素的荧光强度变化,及检测细胞的凋亡情况。
结果
LLC/cMOAT细胞对ADM、VCR、DDP不同程度的耐药,对CTX无明显耐药;洛匹那韦在10. 0μmol/ L浓度范围以下,其对LLC-cMOAT细胞无明显的细胞毒性作用;使用2.5μmol/ L洛匹那韦处理后,LLC/ cMOA T细胞对VCR和DDP敏感性不同程度的增高,当浓度增加至5.0μmol/ L时,LLC/ cMOA T细胞对VCR和DDP的敏感性明显提高;再用2.5μmol/L、5.0μmol/L的洛匹那韦分别处理后ADM在LLC/cMOAT细胞内的蓄积增加,且这种增加呈现有浓度依赖性;通过流式细胞仪检测,细胞周期分析显示,使用洛匹那韦处理0h、4h、8h、16h后,G1期细胞百分比由(42.65±3.75)%分别增至(56.77±2.37)%、(68.13±4.30)%、(70.25±5.12)%,与0h G1期细胞数比较差异显著(p<0.05),这种增加呈时间依赖性;且分别使用2.5μmol/L、5.0μmol/L洛匹那韦处理LLC/ cMOA T细胞48h后,凋亡率增加,并且这种增加呈现时间和浓度依的赖性。
结论
洛匹那韦可以逆转LLC-cMOAT的多药耐药,其逆转机制可能与诱导细胞G1期阻滞,增加细胞内化疗药物蓄积,增强化疗药物诱导的细胞凋亡等有关,且这种诱导细胞凋亡呈现出时间和有剂量的依赖性。
Objective:
To investigate the reversal effects of lopinavir on the multidrug resistance of LLC/ cMOAT cells。
Methods:
The sensitivity of LLC/ CMV and LLC/ cMOAT cells to the several chemotherapeutics and the cytoactive of LLC/ CMV and LLC/ cMOAT cells treated with different concentrations of lopinavir was determined with MTT assay.The inhibition rate of ADM、VCR、CTX and DDP without and with different concentration of lopinavir to LLC/ CMV and LLC/ cMOAT cells were evaluated with MTT assay. The IC50 of different agents was counted. The LLC/ CMV and LLC/ cMOAT cells intracellular concentration of ADM without and with Lopinavir was detected by flow cytometer ( FCM) , The expressions of MRP2 were detected by FCM.
Result:
LLC/ cMOAT cells were resistant to ADM、VCR and DDP to a certain extent but not resistant to CTX.At 10μmol/ L and below, lopinavir was not significantly cytotoxic to LLC/ CMV and LLC/cMOAT cells.After the treatment with 2.5μmol/L lopinavir, the chemosensitivities of LLC/ cMOAT cells to VCR and DDP were enhanced, being much higher when treated with 5.0μmol/L of lopinavir. When treated with 2.5 and 5.0μmol/L lopinavir, ADM accumulation in LLC/cMOAT cells were enhanced significantly with the increase of lopinavir concentration in a concentration-depend manner .Cellular cycle analysis demonstrated that0,4,8,16 hours after co-cultured with lopinavir the amount of cells at G0/G1 phase increased from (42.65±3.75)% at 0h to (70.25±5.12)% at 16h.(p<0.05) ; The cell apoptosis rate was enhanced in a time-and concentration-dependent manner with lopinavir when treated at 2.5 and 5.0μmol/L.
Conclusion:
Lopinavir has reverse effects on the multidrug resistance in LLC/ cMOAT cells, and the reverse effect correlates to lopinavir concentration. The possible mechanism may involve the growth arrest at G1, increase of intracellular drug concentration and promoting apoptosis. The cell apoptosis rate was enhanced in a time-and concentration-dependent manner with lopinavir
探讨洛匹那韦对多药耐药LLC/cMOAT细胞的耐药逆转及可能机制
方法:
应用MTT法分析LLC/ CMV和LLC/ cMOAT细胞株对化疗药物的敏感性;采用MTT法对不同浓度的洛匹那韦对细胞株LLC/ CMV和LLC/ cMOAT处理后,观察细胞的生存状态,并确定其非细胞毒性浓度。并同时用MTT法分别检测阿霉素(ADM)长春新碱(VCR )、环磷酰胺(CTX)、顺铂(DDP)处理上述细胞株后半数抑制浓度( IC50 )。再应用流式细胞术检测加入洛匹那韦后细胞内的化疗药物阿霉素的荧光强度变化,及检测细胞的凋亡情况。
结果
LLC/cMOAT细胞对ADM、VCR、DDP不同程度的耐药,对CTX无明显耐药;洛匹那韦在10. 0μmol/ L浓度范围以下,其对LLC-cMOAT细胞无明显的细胞毒性作用;使用2.5μmol/ L洛匹那韦处理后,LLC/ cMOA T细胞对VCR和DDP敏感性不同程度的增高,当浓度增加至5.0μmol/ L时,LLC/ cMOA T细胞对VCR和DDP的敏感性明显提高;再用2.5μmol/L、5.0μmol/L的洛匹那韦分别处理后ADM在LLC/cMOAT细胞内的蓄积增加,且这种增加呈现有浓度依赖性;通过流式细胞仪检测,细胞周期分析显示,使用洛匹那韦处理0h、4h、8h、16h后,G1期细胞百分比由(42.65±3.75)%分别增至(56.77±2.37)%、(68.13±4.30)%、(70.25±5.12)%,与0h G1期细胞数比较差异显著(p<0.05),这种增加呈时间依赖性;且分别使用2.5μmol/L、5.0μmol/L洛匹那韦处理LLC/ cMOA T细胞48h后,凋亡率增加,并且这种增加呈现时间和浓度依的赖性。
结论
洛匹那韦可以逆转LLC-cMOAT的多药耐药,其逆转机制可能与诱导细胞G1期阻滞,增加细胞内化疗药物蓄积,增强化疗药物诱导的细胞凋亡等有关,且这种诱导细胞凋亡呈现出时间和有剂量的依赖性。
Objective:
To investigate the reversal effects of lopinavir on the multidrug resistance of LLC/ cMOAT cells。
Methods:
The sensitivity of LLC/ CMV and LLC/ cMOAT cells to the several chemotherapeutics and the cytoactive of LLC/ CMV and LLC/ cMOAT cells treated with different concentrations of lopinavir was determined with MTT assay.The inhibition rate of ADM、VCR、CTX and DDP without and with different concentration of lopinavir to LLC/ CMV and LLC/ cMOAT cells were evaluated with MTT assay. The IC50 of different agents was counted. The LLC/ CMV and LLC/ cMOAT cells intracellular concentration of ADM without and with Lopinavir was detected by flow cytometer ( FCM) , The expressions of MRP2 were detected by FCM.
Result:
LLC/ cMOAT cells were resistant to ADM、VCR and DDP to a certain extent but not resistant to CTX.At 10μmol/ L and below, lopinavir was not significantly cytotoxic to LLC/ CMV and LLC/cMOAT cells.After the treatment with 2.5μmol/L lopinavir, the chemosensitivities of LLC/ cMOAT cells to VCR and DDP were enhanced, being much higher when treated with 5.0μmol/L of lopinavir. When treated with 2.5 and 5.0μmol/L lopinavir, ADM accumulation in LLC/cMOAT cells were enhanced significantly with the increase of lopinavir concentration in a concentration-depend manner .Cellular cycle analysis demonstrated that0,4,8,16 hours after co-cultured with lopinavir the amount of cells at G0/G1 phase increased from (42.65±3.75)% at 0h to (70.25±5.12)% at 16h.(p<0.05) ; The cell apoptosis rate was enhanced in a time-and concentration-dependent manner with lopinavir when treated at 2.5 and 5.0μmol/L.
Conclusion:
Lopinavir has reverse effects on the multidrug resistance in LLC/ cMOAT cells, and the reverse effect correlates to lopinavir concentration. The possible mechanism may involve the growth arrest at G1, increase of intracellular drug concentration and promoting apoptosis. The cell apoptosis rate was enhanced in a time-and concentration-dependent manner with lopinavir
引文
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3. Berti E,Carrara M,Ragazzi E,et,al. A comparison of the modulation of antiblastics cytotoxicity by verapamil and dipyridamole in a human colon carcinoma cell line[J]. Int J Oncol, 1999, 15(1): 155-160.
4. List AR, Spier C, Greer J, et al. Phase I/II trial of cyclosporine as a chemotherapy-resi-Stance modifier in acute leukemia[J]. J Chin Oncol, 1993, 11(9): 1652-1660.
5. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-depending transporters[J]. Nat Rev Cancer, 2002, 2(1): 48-58.
6. Rost D, Mahner S, Sugiyamay Y, et a1. Expression and lecali-zation of the multidrug resistanceassociated protein 3 in rat small and large intestine[J]. Am J Physiol Gastrointest Liver Physiol, 2002, 282(4): 720-726.
7. Van Aubel RA, Koenderink J B, Peters JG, et al. Mechanisms and interaction of vinblastine and reduced glutathione transport in membrane vesicles by the rabbit multidrug resistance protein Mrp2 expressed in insect cells[J]. Mol Pharmacol, 1999, 56(4): 714-719.
8. Trauner M, Arrese M, Soroka CJ, et al. The rat canalicular conjugate export pump is down-regulated in intrahepatic and obstructive cholestasis[J]. Gastroenterology,1997, 113: 255-264.
9. Lee JM, Trauner M, Soroka CJ, et al. Expression of the bile salt export pump is maintained after chronic cholestasia in the rat[J]. Gastroenterology, 2000, 118: 163-172.
10. Sandusky GE, Mintze KS, Pratt SE, et al. Expression of multidrug resistanceassociated protein 2(MRP2) in normal human tissues and carcinomas using tissue microarrays. Histopathology, 2002, 41:65-74.
11. Hinoshita E, Uchiumi T, Taguchi K. Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas[J]. Clin Cancer Res, 2000, 6(6): 2401-2407.
12. Suzuki H, Sugiyama Y. Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition[J]. Advanced Drug Delivery, 2002, 54(10): 1311-1331.
13. Iedert B, Materna V, Schadendorf D, et al. Overexpression of cMOAT (MRP2 /ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin[J]. J Invest Dermatol, 2003, 121(1): 172-176.
14.刘刚,华建彪,任宏,等.胃癌组织中多药耐药相关蛋白mRNA的表达及MDR基因产物的检测与其临床病理关系的研究.现代肿瘤医学[J]. 2006, 14(3): 305-307.
15. Lee TC, Ho IC, Lu WJ, et al. Expression of Multidrug in an Arsenic-resistance Human Cell Line[J]. Biol Chem, 2006, 281(27): 18401-18407.
16. K Taniguchi, M Wada, K Kohno, et al. A human canalicular multispecific organic anion transporte(cMOAT)gene is overexpressed in cisplatin-resistant human cancer cell lineswith decreased drug accumulation[J]. Cancer Res, 1996, 56: 4124-4129.
17. Materna.B, Liedert.J, Thomale, et al. Protection of platinum-DNA adductformation and reversal of cisplatin resistance by anti-MRP2 hammerhead ribozymes in human cancer cells[J]. Int J Cancer, 2005, 115: 393-402.
18. T. Huisman, AA. Chhatta, O. van Tellingen, et al. MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid[J]. Int J Cancer, 2005, 116:824-829.
19. K.Koike, T.Kawabe, T.Tanaka, et al. A canalicular multispecific anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells[J]. Cancer Res, 1997, 57: 5475-5479.
20. Kawabe, Z.S. Chen, M. Wada, et al.Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2) [J]. FEBS Lett, 1999, 456:327-331.
21. Lage H. ABC-transporters: implications on drug resistance from microorganisms to human cancers[J]. Int J Antimicrob Agents, 2003, 22(3): 188-199.
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