小白菊内酯对多发性骨髓瘤细胞化疗增敏作用及机制初探
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摘要
第一部分小白菊内酯对多发性骨髓瘤细胞化疗增敏作用
目的:研究小白菊内酯(parthenolide,PTL)联合阿霉素(ADM)或地塞米松(Dex)抗多发性骨髓瘤细胞的作用。
方法:采用多发性骨髓瘤细胞系RPMI8226细胞为研究对象,将PTL(0、0.5、1、2μmol/L)分别与ADM(0、0.01563、0.03125、0.0625、0.0125、0.25、0.5、1、2、4、8μmol/L)、Dex(0、0.001、0.005、0.025、0.125、0.625μmol/L),作用不同时间(48h、72h),应用四甲基偶氮唑蓝(MTT)比色法分析细胞增殖;Annexin-V/PI双染流式细胞术检测细胞凋亡,荧光显微镜下观察丫啶橙/溴化乙锭(AO/EB)染色后的细胞形态变化。
结果:(1)ADM单用48h,RPMI8226细胞的IC50为0.55±0.06μmol/L,与PTL(0.5、1、2μmol/L)联用后,分别降低为0.51±0.04μmol/L、0.28±0.03μmol/L(p<0.05)、0.25±0.02μmol/L (p<0.05);与1μmol/LPTL联用(72h)MM细胞的增殖率由单用Dex(0.005μmol/L)时54±0.9%降至36±1% (p<0.01)。(2)药物作用48h后,Annexin-V/PI双染流式细胞术检测细胞凋亡,空白对照组5±0.63%,单用PTL (2μmol/L)15±3%,单用ADM(0.25μmol/L)20±2.5%,两者联合作用增加为50±7%(与各单用组比,p<0.05)。AO/EB染色荧光显微镜下可见典型的凋亡形态学变化。
结论:PTL可增强ADM、Dex的抗骨髓瘤增殖作用,其增敏效应与增强对MM细胞的凋亡诱导作用有关。
第二部分小白菊内酯对多发性骨髓瘤细胞化疗增敏作用机制研究
目的:目前MM尚缺乏有效的治疗手段。主要的治疗方法是化疗,但化疗副作用比较大,且MM患者容易出现耐药。在上一部分的实验中我们发现PTL对MM细胞有化疗增敏效应,有可能改善MM患者的上述情况。故本部分进一步探讨PTL化疗增敏作用的可能机制,并为以后研究MM的增敏药物提供提示。
方法:以各种浓度梯度PTL及阿霉素(ADM)作用RPMI8226细胞6h后,凝胶蛋白迁移率实验(EMSA)检测核因子κB(NFκB)的活性;48h后,RT-PCR检测细胞Bcl-2、Fas、Survivin mRNA的表达。
结果:PTL可浓度依赖地抑制MM细胞的NFκB活性,1μmol/L以上作用6h可以明显抑制MM细胞的NFκB活性。ADM则能诱导MM细胞NFκB激活,2μmol/L ADM作用6h可使活性增高一倍,而1μmol/L PTL则能抑制其活性诱导作用;0.5～8μmol/L PTL可浓度依赖地抑制Bcl-2、Survivin mRNA的表达,但对Fas表达无明显影响。
结论:PTL可通过抑制MM细胞自身及药物诱导的NFκB活性,下调抗凋亡基因的表达,促进细胞凋亡,增强药物敏感性。
PartⅠParthenolide enhance the antimyeloma effect of Dexamethasone and Adriamycin
Object: To study the combined anti-tumor effect of PTL with Dexamethasone or Adriamycin on MM cell.
Method: Human myeloma cell line RPMI8226 was treated with PTL (0、0.5、1、2μmol/L)combined with ADM(0、0.01563、0.03125、0.0625、0.0125、0.25、0.5、1、2、4、8μmol/L)or Dex(0、0.001、0.005、0.025、0.125、0.625μmol/L),after different times(48h、72h),the cell proliferation was detected by MTT assay, cell apoptosis was detected by Annexin-V/PI with flow cytometry and AO/EB staining.
Result:(1)The IC50 of ADM to RPMI8226 was 0.55±0.06μmol/L ,but when combined with PTL 0.5、1、2μmol/L,it reduced to 0.51±0.04μmol/L、0.28±0.03μmol/L(p<0.05)、0.25±0.02μmol/L (p<0.05),respectively;after 72h treated,compared with the control group,cell proliferation rate of 0.005μmol/L Dex group was 54±0.9%,the combined group(with 1umol/L PTL)reduced to 36±1%(p<0.01).(2)We observed typical apoptosis changes at morphology approach. Apoptosis rates,checked by Annexin-V/PI,were 50±7% (p<0.05) in the combined group,higher than PTL(2μmol/L)group,15±3% and ADM(0.25μmol/L)group ,20±2.5%.
Conclusion:PTL can enhance the anti-myeloma effect of ADM and Dex,which mainly inducing cell apoptosis.
PartⅡThe mechanism of chemosesitization by PTL in MM cell
Object: MM is still an incurable disease. Chemotherapy is often used, but has serious side effects, and may develop to drug resist. We found that PTL may help to overcome these problems. So we investigate the mechanism of chemosensitization via PTL in RPMI8226 cells in this part. And want to show some envidence for the future study of chemosensitization in MM.
Method: After RPMI8226 cell was treated with various concentrations of ADM and PTL,NFκB was measured by EMSA,6h later; the mRNA content of gene Bcl-2、Fas、Survivin were determined by RT-PCR 48h later.
Result: PTL could suppressed the NFκB at a dose dependent manner, 1μmol/L (and above) PTL strongly suppressed the NFκB in RPMI8226 cell after treated 6 h.ADM could activate the NFκB in MM cell. Compared with the control group(ADM 0μmol/L),ADM 2μmol/L doubled the level of NFκB. And PTL (1μmol/L) could also suppress the NFκB enhancing effect of ADM. After treated with 0.5～8μmol/L PTL 48 h,the mRNA contents of Bcl-2、Survivin decreased at a concentration dependent manner, but with no influence on Fas.
Conclusion:PTL can suppress MM cell and drug induced NFκB activation, induce apoptosis and act as a chemosensitizer.
目的:研究小白菊内酯(parthenolide,PTL)联合阿霉素(ADM)或地塞米松(Dex)抗多发性骨髓瘤细胞的作用。
方法:采用多发性骨髓瘤细胞系RPMI8226细胞为研究对象,将PTL(0、0.5、1、2μmol/L)分别与ADM(0、0.01563、0.03125、0.0625、0.0125、0.25、0.5、1、2、4、8μmol/L)、Dex(0、0.001、0.005、0.025、0.125、0.625μmol/L),作用不同时间(48h、72h),应用四甲基偶氮唑蓝(MTT)比色法分析细胞增殖;Annexin-V/PI双染流式细胞术检测细胞凋亡,荧光显微镜下观察丫啶橙/溴化乙锭(AO/EB)染色后的细胞形态变化。
结果:(1)ADM单用48h,RPMI8226细胞的IC50为0.55±0.06μmol/L,与PTL(0.5、1、2μmol/L)联用后,分别降低为0.51±0.04μmol/L、0.28±0.03μmol/L(p<0.05)、0.25±0.02μmol/L (p<0.05);与1μmol/LPTL联用(72h)MM细胞的增殖率由单用Dex(0.005μmol/L)时54±0.9%降至36±1% (p<0.01)。(2)药物作用48h后,Annexin-V/PI双染流式细胞术检测细胞凋亡,空白对照组5±0.63%,单用PTL (2μmol/L)15±3%,单用ADM(0.25μmol/L)20±2.5%,两者联合作用增加为50±7%(与各单用组比,p<0.05)。AO/EB染色荧光显微镜下可见典型的凋亡形态学变化。
结论:PTL可增强ADM、Dex的抗骨髓瘤增殖作用,其增敏效应与增强对MM细胞的凋亡诱导作用有关。
第二部分小白菊内酯对多发性骨髓瘤细胞化疗增敏作用机制研究
目的:目前MM尚缺乏有效的治疗手段。主要的治疗方法是化疗,但化疗副作用比较大,且MM患者容易出现耐药。在上一部分的实验中我们发现PTL对MM细胞有化疗增敏效应,有可能改善MM患者的上述情况。故本部分进一步探讨PTL化疗增敏作用的可能机制,并为以后研究MM的增敏药物提供提示。
方法:以各种浓度梯度PTL及阿霉素(ADM)作用RPMI8226细胞6h后,凝胶蛋白迁移率实验(EMSA)检测核因子κB(NFκB)的活性;48h后,RT-PCR检测细胞Bcl-2、Fas、Survivin mRNA的表达。
结果:PTL可浓度依赖地抑制MM细胞的NFκB活性,1μmol/L以上作用6h可以明显抑制MM细胞的NFκB活性。ADM则能诱导MM细胞NFκB激活,2μmol/L ADM作用6h可使活性增高一倍,而1μmol/L PTL则能抑制其活性诱导作用;0.5～8μmol/L PTL可浓度依赖地抑制Bcl-2、Survivin mRNA的表达,但对Fas表达无明显影响。
结论:PTL可通过抑制MM细胞自身及药物诱导的NFκB活性,下调抗凋亡基因的表达,促进细胞凋亡,增强药物敏感性。
PartⅠParthenolide enhance the antimyeloma effect of Dexamethasone and Adriamycin
Object: To study the combined anti-tumor effect of PTL with Dexamethasone or Adriamycin on MM cell.
Method: Human myeloma cell line RPMI8226 was treated with PTL (0、0.5、1、2μmol/L)combined with ADM(0、0.01563、0.03125、0.0625、0.0125、0.25、0.5、1、2、4、8μmol/L)or Dex(0、0.001、0.005、0.025、0.125、0.625μmol/L),after different times(48h、72h),the cell proliferation was detected by MTT assay, cell apoptosis was detected by Annexin-V/PI with flow cytometry and AO/EB staining.
Result:(1)The IC50 of ADM to RPMI8226 was 0.55±0.06μmol/L ,but when combined with PTL 0.5、1、2μmol/L,it reduced to 0.51±0.04μmol/L、0.28±0.03μmol/L(p<0.05)、0.25±0.02μmol/L (p<0.05),respectively;after 72h treated,compared with the control group,cell proliferation rate of 0.005μmol/L Dex group was 54±0.9%,the combined group(with 1umol/L PTL)reduced to 36±1%(p<0.01).(2)We observed typical apoptosis changes at morphology approach. Apoptosis rates,checked by Annexin-V/PI,were 50±7% (p<0.05) in the combined group,higher than PTL(2μmol/L)group,15±3% and ADM(0.25μmol/L)group ,20±2.5%.
Conclusion:PTL can enhance the anti-myeloma effect of ADM and Dex,which mainly inducing cell apoptosis.
PartⅡThe mechanism of chemosesitization by PTL in MM cell
Object: MM is still an incurable disease. Chemotherapy is often used, but has serious side effects, and may develop to drug resist. We found that PTL may help to overcome these problems. So we investigate the mechanism of chemosensitization via PTL in RPMI8226 cells in this part. And want to show some envidence for the future study of chemosensitization in MM.
Method: After RPMI8226 cell was treated with various concentrations of ADM and PTL,NFκB was measured by EMSA,6h later; the mRNA content of gene Bcl-2、Fas、Survivin were determined by RT-PCR 48h later.
Result: PTL could suppressed the NFκB at a dose dependent manner, 1μmol/L (and above) PTL strongly suppressed the NFκB in RPMI8226 cell after treated 6 h.ADM could activate the NFκB in MM cell. Compared with the control group(ADM 0μmol/L),ADM 2μmol/L doubled the level of NFκB. And PTL (1μmol/L) could also suppress the NFκB enhancing effect of ADM. After treated with 0.5～8μmol/L PTL 48 h,the mRNA contents of Bcl-2、Survivin decreased at a concentration dependent manner, but with no influence on Fas.
Conclusion:PTL can suppress MM cell and drug induced NFκB activation, induce apoptosis and act as a chemosensitizer.
引文
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4. Marcela Oanceaa, Aruna Mani. Apoptosis of Multiple Myeloma. Int J Hematol. 2004 October ; 80(3): 224-231.
5. Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 2002; 2:277-288.
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4. Marcela Oanceaa, Aruna Mani. Apoptosis of Multiple Myeloma. Int J Hematol. 2004 October ; 80(3): 224-231.
5. Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 2002; 2:277-288.
6. Damiano, J. S., Cress, A. E., Hazlehurst, L. A., Shtil, A. A., and Dalton, W. S. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood,.1999, 93: 1658–1667.
7. Gottesman, M. M., Fojo, T., and Bates, S. E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer2002, 2: 48–58.
8. Mitsiades CS, Mitsiades N, Poulaki V, et al. Activation of NF kappaB and upregulationof intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene. 2002;21:5673-5683
9. F.Merchionne, F. Perosa, F. Dammacco. New therapies in multiple myeloma. 2007, 7:83-97.
10. Damiano, J. S., Cress, A. E., Hazlehurst, L. A., Shtil, A. A., and Dalton, W. S. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood, 93: 1658–1667, 1999.
11. Chauhan D,Uchiyama H,Akbarali Y,et a1.Multiple myeloma cell adhesion-induced intedeukin-6 expression in bone marrow stroma cells involves activation of NF-kappa B.Blood, 1996,87:1104-1112.
12. Mitsiades CS, Mitsiades N, Poulaki V, et al. Activation of NFkappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene. 2002; 21:5673-5683.
13. Ogata, A., Chauhan, D., Teoh, G,et al. Interleukin-6 triggers cell growth via the ras-dependent mitogenactivated protein kinase cascade. J. Immunol., 159: 2212–2221, 1997.
14. Chauhan D, Hideshima T, Anderson KC. Apoptotic signaling in multiple myeloma: therapeutic implications. Int J Hematol 2003; 78:114–120.
15. Cooney R N. Suppressors of cytokine signaling (SOCS): inhibitors of the JAK/STAT pathway[J]. Shock, 2002, 17(2): 83- 90.
16. P Neri, P Tassone, M Shammas, et al.Biological pathways and in vivo antitumor activity induced by Atiprimod in myeloma. Leukemia 2007; 21(12):2519-26.
17. Galm O, Wilop S, Reichelt J, et al. DNA methylation changes in multiple myeloma[J]. Leukemia, 2004, 18(10): 1687- 1692.
18. Pappa C, Miyakis S,et al.Serum levels of interleukin-15 and interleukin-10 and their correlation with proliferating cell nuclear antigen in multiple myeloma. Cytokine. 2007; 37(2):171-5
19. Hov H,Holt RU,et al.A selective c-met inhibitor blocks an autocrine hepatocyte growthfactor growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells. Clin Cancer Res. 2004;10(19):6686-94.
20. Mitsades CS,Mitsades N,et al.Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene. 2002;21(37):5673-83.
21. Dent P,Han SL,et al.Advances in oral therapy for multiple myeloma. Lancet Oncol. 2006;7(4):316-25
22. Podar K, Hideshima T, et al. Targeting signaling pathways for the treatment of multiple myeloma. Expert Opin Ther Targets. 2005;9(2):359-81.
23. Drevs J, Medinger M et al. Receptor tyrosine kinases: the main targets for new anticancer therapy.Curr Drug Targets. 2003;4(2):113-21
24. Chang H,StewartImmunohistochemistry accurately predicts FGFR3 aberrant expression and t(4;14) in multiple myeloma.Blood. 2005;106(1):353-5.
25. Hideshima T, Chauhan, et al. The biological sequelae of stroma cell-derived factor-1alpha in multiple myeloma. Mol Cancer Ther. 2002;1(7):539-44.
26. Bonizzi, G. & Karin, M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280–288 (2004).
26. Thomas D. Gilmore。Multiple Myeloma: Lusting for NF-κB. Cancer Cell 200712,95-97
27. Dharminder Chauhan, Teru Hideshima, Proteasome inhibitor therapy in multiple myeloma. Mol Cancer Ther 2005;4(4).:686-92.
28.陈智超,李秋柏,邵菁等。小白菊内酯对多发性骨髓瘤的生长抑制及凋亡诱导作用。中华医学会杂志。2006,86:1993-96.
29. Attaya Suvannasankha,Colin D. Crean, et al. Antimyeloma Effects of a Sesquiterpene Lactone Parthenolide. Clin Cancer Res 2008;14(6)1814-22
30. Monica L. Guzman, Randall M. Rossi, Lilliana Karnischky, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stemand progenitor cells. Blood.2005,105: 4163-4169.
31. Nicholas Mitsiades, Constantine S. et al. Biologic sequelae of nuclear factor–_B blockade in multiple myeloma: therapeutic applications. BLOOD, 1 June 2002 Volume 99, number 11
32. Qing C,Pieter C,Van der Sluis,et a1.,I’he FA/BRCA pathway is involved in melphalan—induced DNA interstrand crosslink repair and accounts for melphalan resistance in multiple myeloma cells.Blood,2005,106:698-705.
33. Je ro me Moreanx,Eric k Eric J,et a1.BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone[J].Blood,2004,103:3148-3157.
34. Yulia N,Pingyan C,Melissa A,et a1.Involvement of Notch一1 signaling in bone marrow stroma mediated denovo drug resistance of myeloma an d other malignant lymphoid cell lines .Blood,2004,103:3503-3510.
35. Stec I,Wright TJ,van Ommen GJ,eta1.WHSC1,a 90 kb SET doma.in—containing gene,expressed in early development and homologous to a Drosophila dysmorphy gene rI1aps in the Wolf-Hirschhom syndrome critical region and is fused to IgH in t(4;
14)multiple myeloma.Hum Mol Genet,l998,7:107l一1082.
36. Ferrara FF,Fail F,Bianchini A,et a1.Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia.Can cer Res ,20ol,61:2.7.
37. Byrd JC,Shinn C,Ravi R,et a1.Depsipeptide(FR901228):a novel therapeutic agent with selective , in vitro activity against human B-cell chronic lymphocytic cells.Blood.1999.94 :1401-1408.
38. Chatterjee M,Jain S,Stuhmer L et a1.STAT3 and MAPK signaling maintains overexpression of the heat shock proteins 90(alpha) and(beta)in multiple myeloma cells,which critically contribute to tumor cell survival.Blood,2007,109:720-728.
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