顺铂耐药卵巢癌细胞化疗药物敏感性及P型铜转运ATP酶、P-糖蛋白表达的研究
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摘要
目的研究顺铂(DDP)、洛铂(LBP)、紫杉醇(PTX)、吉西他滨(GEM)对卵巢癌SKOV3细胞及顺铂耐药SKOV3/DDP细胞增殖的影响,同时检测P型铜转运ATP酶(Copper-transporting P-type adenosine triphosphatese,ATP7B)、P-糖蛋白(P-glycoprotein,P-gp)在两种细胞中的表达,评估其在卵巢癌耐药预测中的作用。
方法在相差显微镜下观察细胞形态的变化;用MTT法测定单药应用、双药联合使用对两种细胞生长的影响;流式细胞仪分析细胞周期和凋亡率的变化;用免疫细胞化学染色法、流式细胞术检测ATP7B、P-gp在两种细胞株中的表达。
结果(1)相同浓度的洛铂、吉西他滨、紫杉醇分别作用于SKOV3细胞和SKOV3/DDP细胞相同时间后,细胞增殖抑制率差异无统计学意义(P＞0.05)。(2)吉西他滨+洛铂、紫杉醇+洛铂、吉西他滨+紫杉醇、紫杉醇+顺铂、吉西他滨+顺铂两药联合组与相应单一用药组相比,能显著抑制两种细胞的生长,其中吉西他滨+洛铂抑制率最高,紫杉醇+洛铂组次之。(3)相同浓度顺铂作用48h后,两种细胞凋亡率不同,SKOV3细胞凋亡率高,两组相比差异有统计学意义(P＜0.05);相同浓度洛铂、紫杉醇、吉西他滨分别作用于两种细胞48h后,细胞凋亡率差异无统计学意义(P＞0.05)。(4)顺铂、洛铂主要作用于细胞G_0/G_1期;紫杉醇作用于细胞G_2/M期;吉西他滨主要作用于S期。(5)ATP7B在SKOV3、SKOV3/DDP细胞中表达分别为1.57±0.47,20.96±1.91,差异有统计学意义(P=0.000),P-gp在两种细胞中的表达分别为1.22±0.15,2.39±1.27,差异无统计学意义(P=0.309)。
结论(1)SKOV3/DDP细胞对紫杉醇、洛铂、吉西他滨无交叉耐药。(2)顺铂、洛铂与紫杉醇、吉西他滨主要作用于不同的细胞周期。(3)吉西他滨+洛铂、紫杉醇+洛铂、吉西他滨+紫杉醇两药联合有高效协同抑制两种细胞生长的作用。(4)体外实验表明顺铂耐药卵巢癌细胞对吉西他滨+洛铂或紫杉醇+洛铂联合敏感。(5)ATP7B的表达可在一定程度上反映卵巢癌细胞对顺铂耐药,对前瞻性预测化疗耐药有一定价值。
Objective This study was to to observe the effect of cisplatin (DDP), lobaplatin (LBP), paclitaxel (PTX) and gemcitabine (GEM) on cell proliferation of human ovarian cancer cell line SKOV3 and its cisplatin-resistant cell line SKOV3/DDP and to investigate the expression of Copper-transporting P-type adenosine triphosphatase (ATP7B) and P-glycoprotein (p-gp) in the two cells, assess their predictive value as indicators of resistance to chemotherapy.
Methods The morphological changes of SKOV3, SKOV3/DDP cells treated by chemotherapeutic drugs were observed under a phase contrast microscope; Methyl thiazolyl tetrazolium (MTT) colorimetric assay was used to detect the differences between the two cells for their sensitivity to chemotherapeutic drugs; the cell cycle and apoptosis rate were measured by flow cytometry. The expression of ATP7B, P-gp was observed by cell immunofluorescence and flow cytometry, respectively.
Results (1) Incubated with the same concentration of lobaplatin, paclitaxel and gemcitabine for the same time, no significant differences in influencing the cell growth inhibitory rate were observed between the SKOV3 and SKOV3/DDP cells (P>0.05). (2) Combination of two chemotherapeutic drugs produced significant anti-proliferation effect on tumor cell growth inhibition when compared with using single drug. Lobaplatin in combination with gemcitabine or paclitaxel had more inhibitory effect on cells. (3) Flow cytometry analysis show that the apoptosis percentage in SKOV3/DDP cells was significantly lower than that in SKOV3 cells after cisplatin treatment for 48 h (p<0.05). Incubated with the same concentration of lobaplatin, paclitaxel and gemcitabine for 48 h, no significant difference in cell apoptotic rate was found between the two groups (P>0.05). (4) Cisplatin and lobaplatin arrest cell cycle in G_0/G_1 phase; Paclitaxel arresting effect is in G_2/M phase and Gemcitabine arresting effect is in S phase. (5) The expression for ATP7B in SKOV3 and SKOV3/DDP cells were 1.57±0.47, 20.96±1.91, respectively. The difference was significant (P=0.000). The expression for p-gp in the two cells were 1.22±0.15 and 2.39±1.27, respectively. There was no significant difference (P=0.309).
Conclusions (1) Ovarian cancer SKOV3/DDP cells showed no sensitivity to cisplatin but they were non-cross-resistant to lobaplatin, paclitaxel and gemcitabine. (2) Cisplatin, lobaplatin, paclitaxel and gemcitabine influenced the cell cycle in different phases. (3) The combined treatments of drugs in chemotherapy can synergistically inhibit the proliferation of cells. (4) In vitro experiments show that it is probably to choose gemcitabine and lobaplatin or paclitaxel plus lobaplatin for the treatment of cisplatin-resistance in ovarian cancer patients. (5) ATP7B expression might serve as an index to evaluate ovarian cancer cisplan-resistance. The test of ATP7B in patients with cisplatin-resistant ovarian cancer may be as reference to choose chemotherapeutic drugs in clinical practice.
方法在相差显微镜下观察细胞形态的变化;用MTT法测定单药应用、双药联合使用对两种细胞生长的影响;流式细胞仪分析细胞周期和凋亡率的变化;用免疫细胞化学染色法、流式细胞术检测ATP7B、P-gp在两种细胞株中的表达。
结果(1)相同浓度的洛铂、吉西他滨、紫杉醇分别作用于SKOV3细胞和SKOV3/DDP细胞相同时间后,细胞增殖抑制率差异无统计学意义(P＞0.05)。(2)吉西他滨+洛铂、紫杉醇+洛铂、吉西他滨+紫杉醇、紫杉醇+顺铂、吉西他滨+顺铂两药联合组与相应单一用药组相比,能显著抑制两种细胞的生长,其中吉西他滨+洛铂抑制率最高,紫杉醇+洛铂组次之。(3)相同浓度顺铂作用48h后,两种细胞凋亡率不同,SKOV3细胞凋亡率高,两组相比差异有统计学意义(P＜0.05);相同浓度洛铂、紫杉醇、吉西他滨分别作用于两种细胞48h后,细胞凋亡率差异无统计学意义(P＞0.05)。(4)顺铂、洛铂主要作用于细胞G_0/G_1期;紫杉醇作用于细胞G_2/M期;吉西他滨主要作用于S期。(5)ATP7B在SKOV3、SKOV3/DDP细胞中表达分别为1.57±0.47,20.96±1.91,差异有统计学意义(P=0.000),P-gp在两种细胞中的表达分别为1.22±0.15,2.39±1.27,差异无统计学意义(P=0.309)。
结论(1)SKOV3/DDP细胞对紫杉醇、洛铂、吉西他滨无交叉耐药。(2)顺铂、洛铂与紫杉醇、吉西他滨主要作用于不同的细胞周期。(3)吉西他滨+洛铂、紫杉醇+洛铂、吉西他滨+紫杉醇两药联合有高效协同抑制两种细胞生长的作用。(4)体外实验表明顺铂耐药卵巢癌细胞对吉西他滨+洛铂或紫杉醇+洛铂联合敏感。(5)ATP7B的表达可在一定程度上反映卵巢癌细胞对顺铂耐药,对前瞻性预测化疗耐药有一定价值。
Objective This study was to to observe the effect of cisplatin (DDP), lobaplatin (LBP), paclitaxel (PTX) and gemcitabine (GEM) on cell proliferation of human ovarian cancer cell line SKOV3 and its cisplatin-resistant cell line SKOV3/DDP and to investigate the expression of Copper-transporting P-type adenosine triphosphatase (ATP7B) and P-glycoprotein (p-gp) in the two cells, assess their predictive value as indicators of resistance to chemotherapy.
Methods The morphological changes of SKOV3, SKOV3/DDP cells treated by chemotherapeutic drugs were observed under a phase contrast microscope; Methyl thiazolyl tetrazolium (MTT) colorimetric assay was used to detect the differences between the two cells for their sensitivity to chemotherapeutic drugs; the cell cycle and apoptosis rate were measured by flow cytometry. The expression of ATP7B, P-gp was observed by cell immunofluorescence and flow cytometry, respectively.
Results (1) Incubated with the same concentration of lobaplatin, paclitaxel and gemcitabine for the same time, no significant differences in influencing the cell growth inhibitory rate were observed between the SKOV3 and SKOV3/DDP cells (P>0.05). (2) Combination of two chemotherapeutic drugs produced significant anti-proliferation effect on tumor cell growth inhibition when compared with using single drug. Lobaplatin in combination with gemcitabine or paclitaxel had more inhibitory effect on cells. (3) Flow cytometry analysis show that the apoptosis percentage in SKOV3/DDP cells was significantly lower than that in SKOV3 cells after cisplatin treatment for 48 h (p<0.05). Incubated with the same concentration of lobaplatin, paclitaxel and gemcitabine for 48 h, no significant difference in cell apoptotic rate was found between the two groups (P>0.05). (4) Cisplatin and lobaplatin arrest cell cycle in G_0/G_1 phase; Paclitaxel arresting effect is in G_2/M phase and Gemcitabine arresting effect is in S phase. (5) The expression for ATP7B in SKOV3 and SKOV3/DDP cells were 1.57±0.47, 20.96±1.91, respectively. The difference was significant (P=0.000). The expression for p-gp in the two cells were 1.22±0.15 and 2.39±1.27, respectively. There was no significant difference (P=0.309).
Conclusions (1) Ovarian cancer SKOV3/DDP cells showed no sensitivity to cisplatin but they were non-cross-resistant to lobaplatin, paclitaxel and gemcitabine. (2) Cisplatin, lobaplatin, paclitaxel and gemcitabine influenced the cell cycle in different phases. (3) The combined treatments of drugs in chemotherapy can synergistically inhibit the proliferation of cells. (4) In vitro experiments show that it is probably to choose gemcitabine and lobaplatin or paclitaxel plus lobaplatin for the treatment of cisplatin-resistance in ovarian cancer patients. (5) ATP7B expression might serve as an index to evaluate ovarian cancer cisplan-resistance. The test of ATP7B in patients with cisplatin-resistant ovarian cancer may be as reference to choose chemotherapeutic drugs in clinical practice.
引文
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[2]Jemal A,Siegel R,Ward E,et al.Cancer statistics,2008,CA Cancer J Clin,008,58:71-96.
[3]Huang F,Tong X,Fu L,et al.Knockdown of STAT3 by shRNA inhibits the growth of CAOV3 ovarian cancer cell line in vitro and in vivo[J].Acta Biochim Biophys Sin (Shanghai),2008,40(6):519-525.
[4]Lu C,Thaker PH,Lin YG,et al.Impact of vessel maturation on antiangiogenic therapy in ovarian cancer[J].Am J Obste Gynecol,2008,198(4):477-479.
[5]Suga S,Kato K,Ohgami T,et al.An inhibitory effect on cell proliferation by blockage of the MAPK/estrogen receptor/MDM2 signal pathway in gynecologic cancer[J].Gynecol Oncol,2007,105(2):341-350.
[6]张丙忠,王静,沙孝珍,等.~(131)I-Anti-c-erb2免疫导向治疗卵巢癌的实验研究[J].中山大学学报:医学科学版,2004,25(20):135-137.
[7]苟文丽,张明慧,曹缵孙.卵巢癌化疗进展[J].国外医学妇幼保健分册,1996,7:72-75.
[8]Ozols RF.Current status of chemotherapy for ovarian cancer[J].Semin Oncol,1995,22(Suppl 12):61.
[9]Swenerton K,Jeffrey J,Stuart G,et al.Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer:A randomized phase Ⅲ study of the National Cancer Institute of Canada Clinical Trials Group[J].J Clin Oncol,1992,10:718.
[10]娄阁.卵巢癌化疗新进展.中国处方药,2007,8:63-66.
[11]Chobanian N,Dietrich CS 3rd.Ovarian Cancer[J].Surg Clin North Am,2008,88:285-299.
[12]Frecdman DA,Levine AJ.Regulation of the p53 protein by mdm2 oncoprotein[J].Cancer Res,1999,59:1-7.
[13]Yakirevich E,Sabo E,Naroditsky I,et al.Multidrug resistance-related phenotype and apoptosis-related protein expression in ovarian serous carcinomas[J].Gynecol Oncol,2006,100(1):152-159.
[14]Tan DS,Ang JE,Kaye SB.Ovarian cancer:can we reverse drug resistance?[J].Adv Exp Med Biol,2008,622:153-167.
[15]Boumendjel A.Anticancer multidrug resistance mediated by MRP1:recent advances in the discovery of reversal agents[J].Medicinal Research Reviews,2005,25(4):453-472.
[16]Duan Z,Brakora KA,Seiden MV.Inhibition of ABCBI(MDR1) and ABCB4(MDR3)expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells[J].Mol Cancer Ther,2004,3(7):833-838.
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