三氧化二砷联合阿霉素对淋巴瘤细胞增殖及凋亡的影响
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摘要
非霍奇金淋巴瘤(NHL)是一种起源于淋巴组织的异质性恶性肿瘤。目前临床应用最广泛的治疗方法是以蒽环类为基础的联合化疗,这些化疗方案对淋巴瘤患者的总体生存率虽有所改善,但大多数患者的治疗效果较差,缓解持续时间短,且毒副反应大,患者不能耐受。体外及动物试验证明三氧化二砷(As_2O_3)具有明显的抗淋巴瘤作用,其作用机制涉及抑制肿瘤细胞增殖,诱导肿瘤细胞凋亡等,其毒副作用小,并与常规化疗药物无交叉耐药性。国内外基础研究显示As_2O_3体外单药及联合其他药物等均可以抑制多种恶性淋巴瘤细胞株的增殖。
本实验从细胞生长增殖、凋亡及凋亡相关蛋白表达等细胞生物学行为的角度,探讨As_2O_3联合阿霉素(ADM)对淋巴瘤细胞株Raji细胞的影响,为临床寻找新的治疗药物和联合化疗方案提供理论依据。我们采用Wright-Giemsa染色法观察细胞凋亡的形态学变化;MTT法分析As_2O_3联合ADM对淋巴瘤细胞增殖抑制作用;采用FCM分析两药联合对细胞凋亡的影响及As_2O_3对细胞内ADM荧光强度影响;用半定量RT-PCR分析细胞内突变型p53的表达水平。结果显示,As_2O_3联合ADM作用细胞24h后,可观察到细胞出现凋亡形态学改变。与As_2O_3或ADM单药组相比,As_2O_3与ADM联合用药可增强对Raji细胞的增殖抑制率,其作用呈浓度和时间依赖性(P＜0.05)。并且As_2O_3与ADM联合组与单药组相比,Raji细胞的凋亡率具有显著性差异(P＜0.05)。同时单药组、联合组中突变型p53的表达水平低于对照组(P＜0.05)。另外加入1μmol/L、2μmol/L As_2O_3后细胞内ADM的荧光强度分别为18.53和18.12,分别增加0.056倍和0.023倍,经统计学分析无明显差异(P＞0.05)。
综上所述,As_2O_3、ADM单药及两种药物的联合体外均可抑制淋巴瘤细胞增殖、诱导凋亡和下调突变型p53;As_2O_3和ADM联合体外有协同抗淋巴瘤作用;As_2O_3对Raji细胞内ADM浓度无显著影响;As_2O_3可增强淋巴瘤细胞的化疗敏感性,其下调突变型p53的表达可能是其分子水平作用机制之一。
Non-Hodgkin's lymphoma is one of heterogeneity hematologic malignant tumors,which is sourced from lymphoid tissue. At present, anthracycline-based regiment is widely used in clinic ,Although it could improve the overal survival rate of lymphoma patients,the treatment evaluation of most patients was poor and remission time was short. Some patients can't tolerance it because of it's serious side effects. Arsenic trioxide(As_2O_3) has shown obvious anti-tumor effect both in vitro and in animal experiments, and the mechanisms are related to cell cycle blocking and apoptosis-inducing effects,etal.It has tolerable side effect and no cross-resistantdrug with other chemodrugs. And domestic and foreign studies suggest that As_2O_3 single or combined other drugs can inhibit proliferation of variety lymphoma cells in vitro.
To provide theoretical proof for new curative chemotherapy drugs and combination chemotherapy programs in clinic, we treated human lymphoma cells Raji with As_2O_3 combined with the traditional chemotherapy drug: adriamycin, and observed the changes of the cells proliferation and cells apoptosis rate. Wright-Giemsa dyeing assay was used to observe apoptosis morphology of lymphoma cells. Detecting proliferation of the cells with As_2O_3 combined with adriamycin by the method of MTT. Flow cytometry(FCM) was used to detect apoptosis of lymphoma and the impact of fluorescene density in the cells by arsenic trioxide. The semi-quantitive RT-PCR was used to detect mutant p53 expression in Raji cells. The results showed that evident change of apoptosis morphology was found in Raji cells after treatment with As_2O_3 and ADM 24 hours. Compared with using alone, the combination of the two drugs can increase the inhibition rates more obviously(P<0.05), and the inhibition rate was related to the concentration and acting time of As_2O_3 (P<0.05). As_2O_3 combined with adriamycin can increase the apoptosis rates of lymphoma cells , and there is obviously difference(P<0.05) ,compared with the two drugs alone. The semi-quantitive RT-PCR showed that the expression of mutant p53 of using alone and combined groups was obviously less than the control(P<0.05). When disposed with 1μmol/L and 2μmol/L As_2O_3, the fluorescene density in Raji cells is 18.53 and 18.12 respectively,increasing 0.056 and 0.023 times respectively,the evident defference of fluorescene density of ADM in the cells not existing by stastically analysizing(P>0.05).
In conclusion, As_2O_3 and ADM using alone or combined can inhibit Raji cells proliferation, induce cells apoptosis and downregulate the expression of mutant p53 in vitro. As_2O_3 combined with adriamycin has synergistic effects on Raji cells in vitro. As_2O_3 cann't increase the concentration of ADM in the Raji cells. As_2O_3 can enhance chemosensitivity of Raji cells by downregulating the expression of mutant p53.
本实验从细胞生长增殖、凋亡及凋亡相关蛋白表达等细胞生物学行为的角度,探讨As_2O_3联合阿霉素(ADM)对淋巴瘤细胞株Raji细胞的影响,为临床寻找新的治疗药物和联合化疗方案提供理论依据。我们采用Wright-Giemsa染色法观察细胞凋亡的形态学变化;MTT法分析As_2O_3联合ADM对淋巴瘤细胞增殖抑制作用;采用FCM分析两药联合对细胞凋亡的影响及As_2O_3对细胞内ADM荧光强度影响;用半定量RT-PCR分析细胞内突变型p53的表达水平。结果显示,As_2O_3联合ADM作用细胞24h后,可观察到细胞出现凋亡形态学改变。与As_2O_3或ADM单药组相比,As_2O_3与ADM联合用药可增强对Raji细胞的增殖抑制率,其作用呈浓度和时间依赖性(P＜0.05)。并且As_2O_3与ADM联合组与单药组相比,Raji细胞的凋亡率具有显著性差异(P＜0.05)。同时单药组、联合组中突变型p53的表达水平低于对照组(P＜0.05)。另外加入1μmol/L、2μmol/L As_2O_3后细胞内ADM的荧光强度分别为18.53和18.12,分别增加0.056倍和0.023倍,经统计学分析无明显差异(P＞0.05)。
综上所述,As_2O_3、ADM单药及两种药物的联合体外均可抑制淋巴瘤细胞增殖、诱导凋亡和下调突变型p53;As_2O_3和ADM联合体外有协同抗淋巴瘤作用;As_2O_3对Raji细胞内ADM浓度无显著影响;As_2O_3可增强淋巴瘤细胞的化疗敏感性,其下调突变型p53的表达可能是其分子水平作用机制之一。
Non-Hodgkin's lymphoma is one of heterogeneity hematologic malignant tumors,which is sourced from lymphoid tissue. At present, anthracycline-based regiment is widely used in clinic ,Although it could improve the overal survival rate of lymphoma patients,the treatment evaluation of most patients was poor and remission time was short. Some patients can't tolerance it because of it's serious side effects. Arsenic trioxide(As_2O_3) has shown obvious anti-tumor effect both in vitro and in animal experiments, and the mechanisms are related to cell cycle blocking and apoptosis-inducing effects,etal.It has tolerable side effect and no cross-resistantdrug with other chemodrugs. And domestic and foreign studies suggest that As_2O_3 single or combined other drugs can inhibit proliferation of variety lymphoma cells in vitro.
To provide theoretical proof for new curative chemotherapy drugs and combination chemotherapy programs in clinic, we treated human lymphoma cells Raji with As_2O_3 combined with the traditional chemotherapy drug: adriamycin, and observed the changes of the cells proliferation and cells apoptosis rate. Wright-Giemsa dyeing assay was used to observe apoptosis morphology of lymphoma cells. Detecting proliferation of the cells with As_2O_3 combined with adriamycin by the method of MTT. Flow cytometry(FCM) was used to detect apoptosis of lymphoma and the impact of fluorescene density in the cells by arsenic trioxide. The semi-quantitive RT-PCR was used to detect mutant p53 expression in Raji cells. The results showed that evident change of apoptosis morphology was found in Raji cells after treatment with As_2O_3 and ADM 24 hours. Compared with using alone, the combination of the two drugs can increase the inhibition rates more obviously(P<0.05), and the inhibition rate was related to the concentration and acting time of As_2O_3 (P<0.05). As_2O_3 combined with adriamycin can increase the apoptosis rates of lymphoma cells , and there is obviously difference(P<0.05) ,compared with the two drugs alone. The semi-quantitive RT-PCR showed that the expression of mutant p53 of using alone and combined groups was obviously less than the control(P<0.05). When disposed with 1μmol/L and 2μmol/L As_2O_3, the fluorescene density in Raji cells is 18.53 and 18.12 respectively,increasing 0.056 and 0.023 times respectively,the evident defference of fluorescene density of ADM in the cells not existing by stastically analysizing(P>0.05).
In conclusion, As_2O_3 and ADM using alone or combined can inhibit Raji cells proliferation, induce cells apoptosis and downregulate the expression of mutant p53 in vitro. As_2O_3 combined with adriamycin has synergistic effects on Raji cells in vitro. As_2O_3 cann't increase the concentration of ADM in the Raji cells. As_2O_3 can enhance chemosensitivity of Raji cells by downregulating the expression of mutant p53.
引文
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