RIP3对胶质母细胞瘤细胞增殖、死亡和化疗敏感性的作用及其作用机制的研究
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摘要
目的
胶质母细胞瘤或多形性胶质母细胞瘤(glioblastoma multiforme, GBM)是最为常见,恶性程度最高的胶质瘤类型。同其他肿瘤一样,GBM的发生、发展以及对各种辅助治疗方式的抵抗与肿瘤细胞内多基因的调节及多种因素相互作用有关。基因治疗被认为是各种恶性肿瘤非常有前景的治疗方式,慢病毒载体介导的基因治疗因其较高的转导效率,较好的操控性,既可感染分裂期也可感染非分裂期细胞,并可将外源基因整合入目的细胞基因组中,长期稳定地表达外源基因,是基因治疗中非常有力的工具；慢病毒载体还可介导RNA干扰,从而持续稳定地抑制靶基因的表达。凋亡是一种程序性细胞死亡,并且已得到了非常广泛而深入地研究。一般认为坏死是一个不可调控的、非程序性的细胞死亡方式,然而,研究证实,坏死可能至少部分是通过程序调控而形成的,这种细胞死亡被命名为程序性坏死。RIP3,属于RIP家族成员,是Ser/Thr蛋白激酶,因其结构中含有RIP家族同源激酶结构域而得名。RIP3在人体多个正常组织中有表达,而在多种恶性肿瘤细胞系中却表达下降或缺失,研究发现,RIP3是程序性细胞坏死过程中的关键蛋白。GBM的发生、发展以及对放化疗的抵抗与肿瘤细胞凋亡功能失调有重要的关系。虽然凋亡过程有缺陷,几乎所有的GBM均表现出不同程度的瘤内坏死。另外,某些抗肿瘤的辅助治疗方式通过诱导肿瘤坏死对多种恶性肿瘤产生良好的治疗效应。诱导肿瘤细胞坏死从而清除肿瘤细胞在近年来逐渐得到重视。然而,通过诱导肿瘤细胞坏死来治疗恶性肿瘤的研究鲜有报道,且尚未有坏死关键因子RIP3对恶性胶质瘤作用的研究。我们通过构建重组人RIP3慢病毒过表达载体和慢病毒shRNA于二扰载体,转导GBM细胞株U251,调控RIP3基因在GBM细胞中的表达,研究RIP3对恶性胶质瘤细胞增殖、死亡的影响及对临床标准的恶性胶质瘤化疗药替莫唑胺敏感性的影响,并探讨其作用机制,为RIP3在胶质母细胞瘤治疗中的应用提供依据。
方法
1.使用Gateway技术构建人RIP3慢病毒过表达载体。使用酶切连接技术构建RIP3慢病毒十扰载体。
2.携带人RIP3基因的重组HIV-1慢病毒与携带RIP3shRNA序列的慢病毒分别转导野生型U251(U251-WT)细胞株,通过G418筛选转导后的U251,Western blot鉴定RIP3的表达情况。
3.使用Annexin V/PI双染法检测U251-WT细胞、U251-RIP3细胞,U251-shRIP3细胞的死亡情况,进一步使用广谱Caspase抑制剂zVAD验证死亡方式。
4.使用CellROXTM Deep Red试剂检测U251-WT细胞、U251-RIP3细胞,U251-shRIP3细胞中ROS的表达水平,研究ROS在RIP3诱导的细胞死亡中的作用。
5.ELISA法检测上述U251-WT细胞、U251-RIP3细胞,U251-shRIP3细胞中的TNF-a的分泌情况,研究其在RIP3诱导的细胞死亡中的作用。
6.MTT检测上述U251-WT细胞、U251-RIP3细胞,U251-shRIP3细胞的生长情况。
7. Western blot法检测上述三株细胞中PI3K/Akt信号通路中关键因子Akt的磷酸化情况。
8.MTT法检测上述三株细胞对TMZ的敏感性差异。使用Annexin V/PI双染法检测U251-WT细胞、U251-RIP3细胞在temozolomide作用下的死亡情况。
9. Western blot法检测U251-WT, U251-RIP3, U251-shRIP3中PARP-1的表达情况。
结果
1.成功构建RIP3慢病毒过表达载体和慢病毒shRNA干扰载体,并与第四代包装质粒共转导包装细胞,获得高达3x108 TU/ml的病毒颗粒。
2.携带人RIP3基因的慢病毒与携带RIP3shRNA序列的慢病毒分别转导U251-WT细胞株,通过G418筛选,分别获得稳定过表达人RIP3基因和RIP3被干扰的细胞株(U251：RIP3及U251-shRIP3)。
3.过表达RIP3的U251细胞出现肿胀样死亡,且这种死亡不被广谱的caspase抑制剂阻断, Annexin V/PI检测进一步证实为死亡细胞PI强阳性。过表达RIP3的U251细胞死亡率明显高于U251-WT及U251-shRIP3,且RIP3过表达诱导U251细胞死亡需要依赖ROS的产生,使用ROS清除剂BHA作用后,其死亡明显减少。
4.与野生型相比,过表达RIP3的U251细胞TNF-α分泌明显增加。而U251-WT与U251-shRIP3的TNF-α分泌无明显差别。
5.在替莫唑胺(TMZ)作用下,过表达RIP3的U251细胞增殖能力明显低于U251-shRIP3和U251-WT细胞。且U251-RIP3的细胞死亡率明显高于U251-WT细胞。
6.相比U251-WT和U251-shRIP3细胞,过表达RIP3的U251细胞株对TMZ作用的敏感性增加,这种作用与RIP3影响PARP-1的表达有关。
结论
1.RIP3可诱导U251出现坏死。RIP3诱导U251细胞TNF-α分泌增加,进一步增加ROS产生从而导致细胞坏死。RIP3通过抑制PI3K/Akt信号通路而影响U251的增殖、生长。RIP3是GBM基因治疗的一个新的的靶分子。
2.RIP3通过影响PARP-1的表达调控U251对TMZ的敏感性,RIP3是一种新的调控胶质母细胞瘤药物敏感性的靶分子。
Background
Glioblastoma or glioblastoma multiforme (glioblastoma multiforme, GBM) is the most encountered and malignant variants of gliomas in clinical practice. As with other tumors, the pathogenesis, development and its resistance to adjuvant treatments of GBM are associated with regulation of multiple genes and interaction of various factors within the tumor cells. Gene therapy is considered as a promising antitumor treatment to various malignancies. Because it has high efficiency of gene transfer, better controllability and it can integrate desired genes into non-dividing cells and dividing cell with stable expression of transgene, lentiviral vector-mediated gene transfer is a very useful way for gene therapy. Lentiviral vector-mediated RNA interference also is widely used to achieve a stable gene silencing in various cell lines. Apoptosis is programmed cell death, and there has been a major emphasis in the literature on the apoptotic form of cell death. Just recently, necrotic cell death is considered as a regulated and controlled process, like apoptosis, termed necroptosis or programmed necrosis. RIP3, a RIP family member, is a Ser/Thr protein kinase and shares homology with the kinase domain within RIP family. It is found that RIP3 is a key protein during the process of programmed cell necrosis. Dysfunction of apoptosis is believed to underlie GBM tumorigenesis and resistance to chemotherapy and radiotherapy. Although there are defects in apoptotic process, nearly all GBMs have different degree of intratumoral necrosis, which does not seem to be associated with the tumor size. In addition, some antitumor therapies have therapeutic effects on a variety of malignant tumors through the induction of tumor cells necrosis. It is a novel way to achieve a better therapeutic effect through the induction of tumor cells necrosis and this idea has gain increasing attention in recent years. Yet, there are limited literature shed light on inducing tumor cell necrosis to combat malignant tumors and no research has been reported to study the RIP3function on GBM. We construct recombinant lentiviral overexpression of human RIP3 vector and shRIP3 vector to modulate the expression of RIP3 in GBM cell lines to study the function and mechanism of RIP3 on proliferation, death and chemosensitivity of GBM cells. This would further reveal the function of RIP3 on GBM and provide basis for applications of RIP3 in GBM treatment.
Methods and Results
Constructing a lentiviral expression vector containing EF1 A-driving human RIP3 gene using Gateway technology and a lentiviral shRNA vector targeting human RIP3 gene using ligation and packaging into viral particles with high titers 1x108 TU/ml. Transducing human RIP3 gene and shRNA targeting human RIP3 into U251 respectively and establishing stable cell lines. U251-RIP3 and U251-shRIP3 by selection with antibiotic. Western blotting showed that the expression lever of RIP3 in U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells. Some U251-RIP3 cells exhibited swelling-like death during culturing. This phenomenon was not inhibited by pan-caspase inhibitor zVAD. Annexin V/PI assay confirmed the death of U251-RIP3 cells was PI positive. Annexin V/PI assay was conducted to study the death rate. Death rate of U251-shRJP3 and U251-WT cells has significant differences with U251-RIP3 cell by Annexin V/PI assay. But there is no significant difference between U251-shRIP3 cells and U251-WT cells. ROS lever was measured by CellROXTM Deep Red Reagent to study the role of ROS in RIP3 induced cell death. ROS level of U251-RIP3 cells is significantly higher than that of U251-shRIP3 cells and U251-WT cells. And U251-shRIP3 did not show a significant difference with U251-WT cells. Death of U251-RIP3 cells is ROS dependent and BHA can reduce the death rate. Recombinant TNF-a do not enhance the death rate of U251-RIP3 cells. ELISA measured the secretion of TNF-a among U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells. TNF-a level of U251-RIP3 cells is significantly higher than that of U251-shRIP3 cells and U251-WT cells. And U251-shRIP3 cells did not show any difference with U251-WT cells. MTT colorimetric assay showed the proliferation of U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells. The proliferation of U251-RIP3 was lower than that of U251-shRIP3 cells and U251-WT cells. Western blotting analyzed the average activation of Akt in U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells. Our result showed that the Akt activation was suppressed in U251-RIP3 cells, whereas, both U251-shRIP3 cells and U251-WT cells had higher level of Akt activation and latter tow group has no significant differences. We analyzed the cell death in U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells in the treatment of temozolomide. The average of cell death rate in the treatment of temozolomide measured by flow cytometry. Death rate of U251-RIP3 cells is much higher than that of U251-WT cells in treatment of temozolomide. MTT colorimetric assay showed that ectopic overexpression of RIP3 in GBM cell line U251 increase its chemosensitivity to temozolomide. U251-shRIP3 cells and U251-WT cells had the same low sensitivity to temozolomide. Western blotting analysis showed that the PARP-1 expression lever in U251-RIP3 cells was lower than that of U251-shRIP3 cells and U251-WT cells. This suggests RIP3 enhance the chemosensitivity of U251 to temozolomide at least partially via its impact on PARP-1.
Conclusion
RIP3 induces necrosis in GBM cell line U251. RIP3 activates the secretion of TNF-a, and then increases ROS production to cause necrosis. RIP3 inhibits proliferation of U251 at least partially by suppressing the Akt pathway. We propose RIP3 is a novel target to GBM gene therapy. RIP3 increases U251 cells sensitivity to temozolomide via the impact on PARP-1, RIP3 may be a targeted molecular to modulate the chemosensitivity of GBM.
胶质母细胞瘤或多形性胶质母细胞瘤(glioblastoma multiforme, GBM)是最为常见,恶性程度最高的胶质瘤类型。同其他肿瘤一样,GBM的发生、发展以及对各种辅助治疗方式的抵抗与肿瘤细胞内多基因的调节及多种因素相互作用有关。基因治疗被认为是各种恶性肿瘤非常有前景的治疗方式,慢病毒载体介导的基因治疗因其较高的转导效率,较好的操控性,既可感染分裂期也可感染非分裂期细胞,并可将外源基因整合入目的细胞基因组中,长期稳定地表达外源基因,是基因治疗中非常有力的工具；慢病毒载体还可介导RNA干扰,从而持续稳定地抑制靶基因的表达。凋亡是一种程序性细胞死亡,并且已得到了非常广泛而深入地研究。一般认为坏死是一个不可调控的、非程序性的细胞死亡方式,然而,研究证实,坏死可能至少部分是通过程序调控而形成的,这种细胞死亡被命名为程序性坏死。RIP3,属于RIP家族成员,是Ser/Thr蛋白激酶,因其结构中含有RIP家族同源激酶结构域而得名。RIP3在人体多个正常组织中有表达,而在多种恶性肿瘤细胞系中却表达下降或缺失,研究发现,RIP3是程序性细胞坏死过程中的关键蛋白。GBM的发生、发展以及对放化疗的抵抗与肿瘤细胞凋亡功能失调有重要的关系。虽然凋亡过程有缺陷,几乎所有的GBM均表现出不同程度的瘤内坏死。另外,某些抗肿瘤的辅助治疗方式通过诱导肿瘤坏死对多种恶性肿瘤产生良好的治疗效应。诱导肿瘤细胞坏死从而清除肿瘤细胞在近年来逐渐得到重视。然而,通过诱导肿瘤细胞坏死来治疗恶性肿瘤的研究鲜有报道,且尚未有坏死关键因子RIP3对恶性胶质瘤作用的研究。我们通过构建重组人RIP3慢病毒过表达载体和慢病毒shRNA于二扰载体,转导GBM细胞株U251,调控RIP3基因在GBM细胞中的表达,研究RIP3对恶性胶质瘤细胞增殖、死亡的影响及对临床标准的恶性胶质瘤化疗药替莫唑胺敏感性的影响,并探讨其作用机制,为RIP3在胶质母细胞瘤治疗中的应用提供依据。
方法
1.使用Gateway技术构建人RIP3慢病毒过表达载体。使用酶切连接技术构建RIP3慢病毒十扰载体。
2.携带人RIP3基因的重组HIV-1慢病毒与携带RIP3shRNA序列的慢病毒分别转导野生型U251(U251-WT)细胞株,通过G418筛选转导后的U251,Western blot鉴定RIP3的表达情况。
3.使用Annexin V/PI双染法检测U251-WT细胞、U251-RIP3细胞,U251-shRIP3细胞的死亡情况,进一步使用广谱Caspase抑制剂zVAD验证死亡方式。
4.使用CellROXTM Deep Red试剂检测U251-WT细胞、U251-RIP3细胞,U251-shRIP3细胞中ROS的表达水平,研究ROS在RIP3诱导的细胞死亡中的作用。
5.ELISA法检测上述U251-WT细胞、U251-RIP3细胞,U251-shRIP3细胞中的TNF-a的分泌情况,研究其在RIP3诱导的细胞死亡中的作用。
6.MTT检测上述U251-WT细胞、U251-RIP3细胞,U251-shRIP3细胞的生长情况。
7. Western blot法检测上述三株细胞中PI3K/Akt信号通路中关键因子Akt的磷酸化情况。
8.MTT法检测上述三株细胞对TMZ的敏感性差异。使用Annexin V/PI双染法检测U251-WT细胞、U251-RIP3细胞在temozolomide作用下的死亡情况。
9. Western blot法检测U251-WT, U251-RIP3, U251-shRIP3中PARP-1的表达情况。
结果
1.成功构建RIP3慢病毒过表达载体和慢病毒shRNA干扰载体,并与第四代包装质粒共转导包装细胞,获得高达3x108 TU/ml的病毒颗粒。
2.携带人RIP3基因的慢病毒与携带RIP3shRNA序列的慢病毒分别转导U251-WT细胞株,通过G418筛选,分别获得稳定过表达人RIP3基因和RIP3被干扰的细胞株(U251：RIP3及U251-shRIP3)。
3.过表达RIP3的U251细胞出现肿胀样死亡,且这种死亡不被广谱的caspase抑制剂阻断, Annexin V/PI检测进一步证实为死亡细胞PI强阳性。过表达RIP3的U251细胞死亡率明显高于U251-WT及U251-shRIP3,且RIP3过表达诱导U251细胞死亡需要依赖ROS的产生,使用ROS清除剂BHA作用后,其死亡明显减少。
4.与野生型相比,过表达RIP3的U251细胞TNF-α分泌明显增加。而U251-WT与U251-shRIP3的TNF-α分泌无明显差别。
5.在替莫唑胺(TMZ)作用下,过表达RIP3的U251细胞增殖能力明显低于U251-shRIP3和U251-WT细胞。且U251-RIP3的细胞死亡率明显高于U251-WT细胞。
6.相比U251-WT和U251-shRIP3细胞,过表达RIP3的U251细胞株对TMZ作用的敏感性增加,这种作用与RIP3影响PARP-1的表达有关。
结论
1.RIP3可诱导U251出现坏死。RIP3诱导U251细胞TNF-α分泌增加,进一步增加ROS产生从而导致细胞坏死。RIP3通过抑制PI3K/Akt信号通路而影响U251的增殖、生长。RIP3是GBM基因治疗的一个新的的靶分子。
2.RIP3通过影响PARP-1的表达调控U251对TMZ的敏感性,RIP3是一种新的调控胶质母细胞瘤药物敏感性的靶分子。
Background
Glioblastoma or glioblastoma multiforme (glioblastoma multiforme, GBM) is the most encountered and malignant variants of gliomas in clinical practice. As with other tumors, the pathogenesis, development and its resistance to adjuvant treatments of GBM are associated with regulation of multiple genes and interaction of various factors within the tumor cells. Gene therapy is considered as a promising antitumor treatment to various malignancies. Because it has high efficiency of gene transfer, better controllability and it can integrate desired genes into non-dividing cells and dividing cell with stable expression of transgene, lentiviral vector-mediated gene transfer is a very useful way for gene therapy. Lentiviral vector-mediated RNA interference also is widely used to achieve a stable gene silencing in various cell lines. Apoptosis is programmed cell death, and there has been a major emphasis in the literature on the apoptotic form of cell death. Just recently, necrotic cell death is considered as a regulated and controlled process, like apoptosis, termed necroptosis or programmed necrosis. RIP3, a RIP family member, is a Ser/Thr protein kinase and shares homology with the kinase domain within RIP family. It is found that RIP3 is a key protein during the process of programmed cell necrosis. Dysfunction of apoptosis is believed to underlie GBM tumorigenesis and resistance to chemotherapy and radiotherapy. Although there are defects in apoptotic process, nearly all GBMs have different degree of intratumoral necrosis, which does not seem to be associated with the tumor size. In addition, some antitumor therapies have therapeutic effects on a variety of malignant tumors through the induction of tumor cells necrosis. It is a novel way to achieve a better therapeutic effect through the induction of tumor cells necrosis and this idea has gain increasing attention in recent years. Yet, there are limited literature shed light on inducing tumor cell necrosis to combat malignant tumors and no research has been reported to study the RIP3function on GBM. We construct recombinant lentiviral overexpression of human RIP3 vector and shRIP3 vector to modulate the expression of RIP3 in GBM cell lines to study the function and mechanism of RIP3 on proliferation, death and chemosensitivity of GBM cells. This would further reveal the function of RIP3 on GBM and provide basis for applications of RIP3 in GBM treatment.
Methods and Results
Constructing a lentiviral expression vector containing EF1 A-driving human RIP3 gene using Gateway technology and a lentiviral shRNA vector targeting human RIP3 gene using ligation and packaging into viral particles with high titers 1x108 TU/ml. Transducing human RIP3 gene and shRNA targeting human RIP3 into U251 respectively and establishing stable cell lines. U251-RIP3 and U251-shRIP3 by selection with antibiotic. Western blotting showed that the expression lever of RIP3 in U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells. Some U251-RIP3 cells exhibited swelling-like death during culturing. This phenomenon was not inhibited by pan-caspase inhibitor zVAD. Annexin V/PI assay confirmed the death of U251-RIP3 cells was PI positive. Annexin V/PI assay was conducted to study the death rate. Death rate of U251-shRJP3 and U251-WT cells has significant differences with U251-RIP3 cell by Annexin V/PI assay. But there is no significant difference between U251-shRIP3 cells and U251-WT cells. ROS lever was measured by CellROXTM Deep Red Reagent to study the role of ROS in RIP3 induced cell death. ROS level of U251-RIP3 cells is significantly higher than that of U251-shRIP3 cells and U251-WT cells. And U251-shRIP3 did not show a significant difference with U251-WT cells. Death of U251-RIP3 cells is ROS dependent and BHA can reduce the death rate. Recombinant TNF-a do not enhance the death rate of U251-RIP3 cells. ELISA measured the secretion of TNF-a among U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells. TNF-a level of U251-RIP3 cells is significantly higher than that of U251-shRIP3 cells and U251-WT cells. And U251-shRIP3 cells did not show any difference with U251-WT cells. MTT colorimetric assay showed the proliferation of U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells. The proliferation of U251-RIP3 was lower than that of U251-shRIP3 cells and U251-WT cells. Western blotting analyzed the average activation of Akt in U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells. Our result showed that the Akt activation was suppressed in U251-RIP3 cells, whereas, both U251-shRIP3 cells and U251-WT cells had higher level of Akt activation and latter tow group has no significant differences. We analyzed the cell death in U251-RIP3 cells, U251-shRIP3 cells and U251-WT cells in the treatment of temozolomide. The average of cell death rate in the treatment of temozolomide measured by flow cytometry. Death rate of U251-RIP3 cells is much higher than that of U251-WT cells in treatment of temozolomide. MTT colorimetric assay showed that ectopic overexpression of RIP3 in GBM cell line U251 increase its chemosensitivity to temozolomide. U251-shRIP3 cells and U251-WT cells had the same low sensitivity to temozolomide. Western blotting analysis showed that the PARP-1 expression lever in U251-RIP3 cells was lower than that of U251-shRIP3 cells and U251-WT cells. This suggests RIP3 enhance the chemosensitivity of U251 to temozolomide at least partially via its impact on PARP-1.
Conclusion
RIP3 induces necrosis in GBM cell line U251. RIP3 activates the secretion of TNF-a, and then increases ROS production to cause necrosis. RIP3 inhibits proliferation of U251 at least partially by suppressing the Akt pathway. We propose RIP3 is a novel target to GBM gene therapy. RIP3 increases U251 cells sensitivity to temozolomide via the impact on PARP-1, RIP3 may be a targeted molecular to modulate the chemosensitivity of GBM.
引文
[1]Wen PY,Kesari S. Malignant gliomas in adults. N Engl J Med 2008; 359(5): 492-507.
[2]Chiocca EA. Gene therapy:a primer for neurosurgeons. Neurosurgery 2003; 53(2):364-373; discussion 373.
[3]Germano IM,Binello E. Gene therapy as an adjuvant treatment for malignant gliomas:from bench to bedside. J Neurooncol 2009; 93(1):79-87.
[4]Lefranc F, Facchini V,Kiss R. Proautophagic drugs:a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 2007; 12(12):1395-1403.
[5]Krakstad C,Chekenya M. Survival signalling and apoptosis resistance in glioblastomas:opportunities for targeted therapeutics. Mol Cancer 2010; 9(p: 135.
[6]Raza SM, Lang FF, Aggarwal BB, et al. Necrosis and glioblastoma:a friend or a foe? A review and a hypothesis. Neurosurgery 2002; 51(1):2-12; discussion 12-13.
[7]Hammoud MA, Sawaya R, Shi W, et al. Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J Neurooncol 1996; 27(1): 65-73.
[8]Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme:prognosis, extent of resection, and survival. J Neurosurg 2001; 95(2):190-198.
[9]Hotchkiss RS, Strasser A, McDunn JE, et al. Cell death. N Engl J Med 2009; 361(16):1570-1583.
[10]Klionsky DJ. Autophagy:from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8(11):931-937.
[11]Kroemer G, Galluzzi L, Vandenabeele P, et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009; 16(1):3-11.
[12]Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267(5203):1456-1462.
[13]Reed JC. Drug insight:cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Clin Pract Oncol 2006; 3(7):388-398.
[14]Green DR,Kroemer G. Pharmacological manipulation of cell death:clinical applications in sight? J Clin Invest 2005; 115(10):2610-2617.
[15]Galluzzi L,Kroemer G. Necroptosis:a specialized pathway of programmed necrosis. Cell 2008; 135(7):1161-1163.
[16]Hitomi J, Christofferson DE, Ng A, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 2008; 135(7):1311-1323.
[17]Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009; 137(6):1112-1123.
[18]Zhang DW, Shao J, Lin J, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009; 325(5938):332-336.
[19]He S, Wang L, Miao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009; 137(6):1100-1111.
[20]Sun X, Lee J, Navas T, et al. RIP3, a novel apoptosis-inducing kinase. J Biol Chem 1999; 274(24):16871-16875.
[21]Yu PW, Huang BC, Shen M, et al. Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB. Curr Biol 1999; 9(10):539-542.
[22]Kasof GM, Prosser JC, Liu D, et al. The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria. FEBS Lett 2000; 473(3):285-291.
[23]Newton K, Sun X.Dixit VM. Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol Cell Biol 2004; 24(4):1464-1469.
[24]Reifenberger G,Collins VP. Pathology and molecular genetics of astrocytic gliomas. J Mol Med 2004; 82(10):656-670.
[25]Sonoda Y, Ozawa T, Aldape KD, et al. Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res 2001; 61(18):6674-6678.
[26]Holland EC, Celestino J, Dai C, et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 2000; 25(1):55-57.
[27]Bjornsti MA,Houghton PJ. The TOR pathway:a target for cancer therapy. Nat Rev Cancer 2004; 4(5):335-348.
[28]Gallia GL, Tyler BM, Hann CL, et al. Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther 2009; 8(2): 386-393.
[29]Liu XH, Yu EZ, Li YY, et al. RNA interference targeting Akt promotes apoptosis in hypoxia-exposed human neuroblastoma cells. Brain Res 2006; 1070(1):24-30.
[30]Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987-996.
[31]Newlands ES, Stevens MF, Wedge SR, et al. Temozolomide:a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 1997; 23(1):35-61.
[32]Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10):997-1003.
[33]Marchesi F, Turriziani M, Tortorelli G, et al. Triazene compounds:mechanism of action and related DNA repair systems. Pharmacol Res 2007; 56(4): 275-287.
[34]Villano JL, Seery TE,Bressler LR. Temozolomide in malignant gliomas: current use and future targets. Cancer Chemother Pharmacol 2009; 64(4): 647-655.
[35]Wharton SB, McNelis U, Bell HS, et al. Expression of poly(ADP-ribose) polymerase and distribution of poly(ADP-ribosyl)ation in glioblastoma and in a glioma multicellular tumour spheroid model. Neuropathol Appl Neurobiol 2000; 26(6):528-535.
[36]Barton VN, Donson AM, Kleinschmidt-DeMasters BK, et al. PARP1 expression in pediatric central nervous system tumors. Pediatr Blood Cancer 2009; 53(7):1227-1230.
[37]Virag L,Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 2002; 54(3):375-429.
[38]Miknyoczki S, Chang H, Grobelny J, et al. The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. Mol Cancer Ther 2007; 6(8):2290-2302.
[39]Donawho CK, Luo Y, Penning TD, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 2007; 13(9):2728-2737.
[40]Plummer R, Jones C, Middleton M, et al. Phase Ⅰ study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 2008; 14(23):7917-7923.
[41]Daniel RA, Rozanska AL, Thomas HD, et al. Inhibition of poly(ADP-ribose) polymerase-1 enhances temozolomide and topotecan activity against childhood neuroblastoma. Clin Cancer Res 2009; 15(4):1241-1249.
[42]Iwami K, Natsume A,Wakabayashi T. Gene therapy for high-grade glioma. Neurol Med Chir (Tokyo) 2010; 50(9):727-736.
[43]Guo SW, Che HM,Li WZ. Anti-tumor effect of lentivirus-mediated gene transfer of alphastatin on Human glioma. Cancer Sci 2011.
[44]Manjunath N, Wu H, Subramanya S, et al. Lentiviral delivery of short hairpin RNAs. Adv Drug Deliv Rev 2009; 61(9):732-745.
[45]Lever AM, Strappe PM,Zhao J. Lentiviral vectors. J Biomed Sci 2004:11(4): 439-449.
[46]Martin-Rendon E, Azzouz M,Mazarakis ND. Lentiviral vectors for the treatment of neurodegenerative diseases. Curr Opin Mol Ther 2001; 3(5): 476-481.
[47]Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003; 348(3):255-256.
[48]Ralph GS, Binley K, Wong LF, et al. Gene therapy for neurodegenerative and ocular diseases using lentiviral vectors. Clin Sci (Lond) 2006; 110(1):37-46.
[49]Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272(5259):263-267.
[50]Wiznerowicz M,Trono D. Harnessing HIV for therapy, basic research and biotechnology. Trends Biotechnol 2005; 23(1):42-47.
[51]Cockrell AS.Kafri T. Gene delivery by lentivirus vectors. Mol Biotechnol 2007; 36(3):184-204.
[52]Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114(2): 97-109.
[53]Stiles B, Gilman V, Khanzenzon N, et al. Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis. Mol Cell Biol 2002; 22(11): 3842-3851.
[54]Kandel ES, Skeen J, Majewski N, et al. Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage. Mol Cell Biol 2002; 22(22):7831-7841.
[55]Riemenschneider MJ, Betensky RA, Pasedag SM, et al. AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling. Cancer Res 2006; 66(11):5618-5623.
[56]Suzuki Y, Shirai K, Oka K, et al. Higher pAkt expression predicts a significant worse prognosis in glioblastomas. J Radiat Res (Tokyo) 2010; 51(3):343-348.
[57]Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007; 21(21): 2683-2710.
[58]Majno G,Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. AmJ Pathol 1995; 146(1):3-15.
[59]Adams JM,Cory S. Bcl-2-regulated apoptosis:mechanism and therapeutic potential. Curr Opin Immunol 2007; 19(5):488-496.
[60]Marsden VS,Strasser A. Control of apoptosis in the immune system:Bcl-2, BH3-only proteins and more. Annu Rev Immunol 2003; 21(71-105.
[61]Golstein P,Kroemer G. Cell death by necrosis:towards a molecular definition. Trends Biochem Sci 2007; 32(1):37-43.
[62]Zong WX,Thompson CB. Necrotic death as a cell fate. Genes Dev 2006; 20(1): 1-15.
[63]Galluzzi L, Kepp O,Kroemer G. RIP kinases initiate programmed necrosis. J Mol Cell Biol 2009:1(1):8-10.
[64]Petersen SL, Wang L, Yalcin-Chin A, et al. Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 2007; 12(5):445-456.
[65]Van Herreweghe F, Festjens N, Declercq W, et al. Tumor necrosis factor-mediated cell death:to break or to burst, that's the question. Cell Mol Life Sci 2010; 67(10):1567-1579.
[66]Mabrouk GM, Ali EM, El-Rehany MA, et al. TGF-betal, TNF-alpha and cytochrome c in human astrocytic tumors:a short-term follow up and correlation with survival. Clin Biochem 2007; 40(3-4):255-260.
[67]Chen QM, Bartholomew JC, Campisi J, et al. Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts:p53 and Rb control G1 arrest but not cell replication. Biochem J 1998; 332 (Pt 1)(43-50.
[68]Irani K, Xia Y, Zweier JL, et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 1997; 275(5306):1649-1652.
[69]Oh SY, Sohn YW, Park JW, et al. Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species mediated damage. Mol Cancer Ther 2007; 6(8):2178-2187.
[70]Brandsma D, Stalpers L, Taal W, et al. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008; 9(5):453-461.
[71]Minniti G, Armosini V, Salvati M, et al. Fractionated stereotactic reirradiation and concurrent temozolomide in patients with recurrent glioblastoma. J Neurooncol 2010.
[72]Lefranc F,Kiss R. Autophagy, the Trojan horse to combat glioblastomas. Neurosurg Focus 2006; 20(4) p:E7.
[73]Baker SD, Wirth M, Statkevich P, et al. Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res 1999; 5(2):309-317.
[74]Kanzawa T, Bedwell J, Kondo Y, et al. Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide. J Neurosurg 2003; 99(6): 1047-1052.
[75]Roos WP, Batista LF, Naumann SC, et al. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 2007; 26(2):186-197.
[76]Takeuchi H, Kondo Y, Fujiwara K, et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 2005; 65(8):3336-3346.
[77]Kanzawa T, Germano IM, Komata T, et al. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 2004; 11(4):448-457.
[78]Tolcher AW, Gerson SL, Denis L, et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 2003; 88(7):1004-1011.
[79]Turriziani M, Caporaso P, Bonmassar L, et al.06-(4-bromothenyl)guanine (PaTrin-2), a novel inhibitor of O6-alkylguanine DNA alkyl-transferase, increases the inhibitory activity of temozolomide against human acute leukaemia cells in vitro. Pharmacol Res 2006; 53(4):317-323.
[80]Rouleau M, Patel A, Hendzel MJ, et al. PARP inhibition:PARP1 and beyond. Nat Rev Cancer 2010; 10(4):293-301.
[81]Burkle A. Physiology and pathophysiology of poly(ADP-ribosyl)ation. Bioessays 2001; 23(9):795-806.
[82]Tomoda T, Kurashige T, Moriki T, et al. Enhanced expression of poly(ADP-ribose) synthetase gene in malignant lymphoma. Am J Hematol 1991; 37(4):223-227.
[83]Shiobara M, Miyazaki M, Ito H, et al. Enhanced polyadenosine diphosphate-ribosylation in cirrhotic liver and carcinoma tissues in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2001; 16(3):338-344.
[84]Fukushima M, Kuzuya K, Ota K, et al. Poly(ADP-ribose) synthesis in human cervical cancer cell-diagnostic cytological usefulness. Cancer Lett 1981; 14(3): 227-236.
[85]Wielckens K, Garbrecht M, Kittler M, et al. ADP-ribosylation of nuclear proteins in normal lymphocytes and in low-grade malignant non-Hodgkin lymphoma cells. Eur J Biochem 1980; 104(1):279-287.
[86]de Murcia JM, Niedergang C, Trucco C, et al. Requirement of poly (ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A 1997; 94(14):7303-7307.
[87]Schreiber V, Ame JC, Dolle P, et al. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 2002; 277(25):23028-23036.
[1]Wen PY,Kesari S. Malignant gliomas in adults. N Engl J Med 2008; 359(5): 492-507.
[2]Lefranc F, Facchini V,Kiss R. Proautophagic drugs:a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 2007; 12(12):1395-1403.
[3]Krakstad C,Chekenya M. Survival signalling and apoptosis resistance in glioblastomas:opportunities for targeted therapeutics. Mol Cancer 2010; 9(p: 135.
[4]Raza SM, Lang FF, Aggarwal BB, et al. Necrosis and glioblastoma:a friend or a foe? A review and a hypothesis. Neurosurgery 2002; 51(1):2-12; discussion 12-13.
[5]Hammoud MA, Sawaya R, Shi WM, et al. Prognostic significance of preoperative MRI scans in glioblastoma multiforme. Journal of Neuro-Oncology 1996; 27(1):65-73.
[6]Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme:prognosis, extent of resection, and survival. J Neurosurg 2001; 95(2):190-198.
[7]Jensen RL. Brain tumor hypoxia:tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol 2009; 92(3): 317-335.
[8]Hotchkiss RS, Strasser A, McDunn JE, et al. Cell death. N Engl J Med 2009; 361(16):1570-1583.
[9]Klionsky DJ. Autophagy:from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8(11):931-937.
[10]Kroemer G,Jaattela M. Lysosomes and autophagy in cell death control. Nat Rev Cancer 2005; 5(11):886-897.
[11]Levine B,Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol 2007; 7(10):767-777.
[12]Kroemer G, Galluzzi L, Vandenabeele P, et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009; 16(1):3-11.
[13]Majno G,Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 1995; 146(1):3-15.
[14]Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267(5203):1456-1462.
[15]Reed JC. Drug insight:cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Clin Pract Oncol 2006; 3(7):388-398.
[16]Green DR,Kroemer G. Pharmacological manipulation of cell death:clinical applications in sight? J Clin Invest 2005; 115(10):2610-2617.
[17]Hitomi J, Christofferson DE, Ng A, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 2008; 135(7):1311-1323.
[18]Zong WX,Thompson CB. Necrotic death as a cell fate. Genes Dev 2006; 20(1): 1-15.
[19]Galluzzi L, Aaronson SA, Abrams J, et al. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ 2009; 16(8):1093-1107.
[20]Festjens N, Vanden Berghe T,Vandenabeele P. Necrosis, a well-orchestrated form of cell demise:signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 2006; 1757(9-10):1371-1387.
[21]Kerr JF, Wyllie AH,Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26(4): 239-257.
[22]Adams JM,Cory S. Bcl-2-regulated apoptosis:mechanism and therapeutic potential. Curr Opin Immunol 2007; 19(5):488-496.
[23]Marsden VS,Strasser A. Control of apoptosis in the immune system:Bcl-2, BH3-only proteins and more. Annu Rev Immunol 2003; 21(71-105.
[24]Golstein P,Kroemer G. Cell death by necrosis:towards a molecular definition. Trends Biochem Sci 2007; 32(1):37-43.
[25]Yuan J, Shaham S, Ledoux S, et al. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 1993; 75(4):641-652.
[26]Salmena L, Lemmers B, Hakem A, et al. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev 2003; 17(7):883-895.
[27]Green DR. Apoptotic pathways:ten minutes to dead. Cell 2005; 121(5): 671-674.
[28]Newton K, Harris AW. Bath ML. et al. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J 1998; 17(3):706-718.
[29]Yu JW,Shi Y. FLIP and the death effector domain family. Oncogene 2008; 27(48):6216-6227.
[30]Wang X. The expanding role of mitochondria in apoptosis. Genes Dev 2001; 15(22):2922-2933.
[31]Strasser A. The role of BH3-only proteins in the immune system. Nat Rev Immunol 2005; 5(3):189-200.
[32]Goldstein JC, Munoz-Pinedo C, Ricci JE, et al. Cytochrome c is released in a single step during apoptosis. Cell Death Differ 2005; 12(5):453-462.
[33]Hughes PD, Belz GT, Fortner KA, et al. Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Immunity 2008; 28(2):197-205.
[34]Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007; 21(21): 2683-2710.
[35]Weller M, Malipiero U, Aguzzi A, et al. Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. J Clin Invest 1995; 95(6):2633-2643.
[36]Roth W, Isenmann S, Naumann U, et al. Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem Biophys Res Commun 1999; 265(2): 479-483.
[37]Nagane M, Pan G, Weddle JJ, et al. Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 2000; 60(4):847-853.
[38]Rohn TA, Wagenknecht B, Roth W, et al. CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. Oncogene 2001; 20(31): 4128-4137.
[39]Roth W, Isenmann S, Nakamura M, et al. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Res 2001; 61(6):2759-2765.
[40]Kuijlen JM, Mooij JJ, Platteel I, et al. TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme. J Neurooncol 2006; 78(2):161-171.
[41]Fulda S, Wick W, Weller M, et al. Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 2002; 8(8):808-815.
[42]Green DR,Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305(5684):626-629.
[43]Krajewski S, Krajewska M, Ehrmann J, et al. Immunohistochemical analysis of Bcl-2, Bcl-X, Mcl-1, and Bax in tumors of central and peripheral nervous system origin. Am J Pathol 1997; 150(3):805-814.
[44]Strik H, Deininger M, Streffer J, et al. BCL-2 family protein expression in initial and recurrent glioblastomas:modulation by radiochemotherapy. J Neurol Neurosurg Psychiatry 1999; 67(6):763-768.
[45]Ruano Y, Mollejo M, Camacho FI, et al. Identification of survival-related genes of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma multiforme. Cancer 2008; 112(7):1575-1584.
[46]Wick W, Wagner S, Kerkau S, et al. BCL-2 promotes migration and invasiveness of human glioma cells. FEBS Lett 1998; 440(3):419-424.
[47]Stegh AH, Kim H, Bachoo RM, et al. Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma. Genes Dev 2007; 21(1):98-111.
[48]Stegh AH, Kesari S, Mahoney JE. et al. Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma. Proc Natl Acad Sci U S A 2008; 105(31):10703-10708.
[49]Ashford TP,Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol 1962; 12(198-202.
[50]Watanabe E, Muenzer JT. Hawkins WG, et al. Sepsis induces extensive autophagic vacuolization in hepatocytes:a clinical and laboratory-based study. Lab Invest 2009; 89(5):549-561.
[51]Espert L, Denizot M, Grimaldi M, et al. Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J Clin Invest 2006; 116(8):2161-2172.
[52]Levine B,Yuan J. Autophagy in cell death:an innocent convict? J Clin Invest 2005; 115(10):2679-2688.
[53]Galluzzi L, Maiuri MC, Vitale I, et al. Cell death modalities:classification and pathophysiological implications. Cell Death Differ 2007; 14(7):1237-1243.
[54]Amaravadi RK,Thompson CB. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 2007; 13(24):7271-7279.
[55]Marx J. Autophagy:is it cancer's friend or foe? Science 2006; 312(5777): 1160-1161.
[56]Maiuri MC, Tasdemir E, Criollo A, et al. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ 2009; 16(1):87-93.
[57]Takahashi Y, Coppola D, Matsushita N, et al. Bif-1 interacts with Beelin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007; 9(10):1142-1151.
[58]Ahn CH, Jeong EG, Lee JW, et al. Expression of beclin-1, an autophagy-related protein, in gastric and colorectal cancers. APMIS 2007; 115(12):1344-1349.
[59]Liang C, Feng P, Ku B, et al. Autophagic and tumour suppressor activity of a novel Beclinl-binding protein UVRAG. Nat Cell Biol 2006; 8(7):688-699.
[60]Desai BN, Myers BR,Schreiber SL. FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc Natl Acad Sci U S A 2002; 99(7):4319-4324.
[61]Takeuchi H, Kondo Y, Fujiwara K, et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 2005; 65(8):3336-3346.
[62]Eshleman JS, Carlson BL. Mladek AC, et al. Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 2002; 62(24):7291-7297.
[63]Takeuchi H, Kanzawa T, Kondo Y, et al. Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells. Br J Cancer 2004; 90(5):1069-1075.
[64]Lefranc F, Brotchi J,Kiss R. Possible future issues in the treatment of glioblastomas:special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 2005; 23(10): 2411-2422.
[65]Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987-996.
[66]Kanzawa T, Germano IM, Komata T, et al. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 2004; 11(4):448-457.
[67]Kanzawa T, Bedwell J, Kondo Y, et al. Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide. J Neurosurg 2003; 99(6): 1047-1052.
[68]Galluzzi L,Kroemer G. Necroptosis:a specialized pathway of programmed necrosis. Cell 2008; 135(7):1161-1163.
[69]Nicotera P,Melino G. Regulation of the apoptosis-necrosis switch. Oncogene 2004; 23(16):2757-2765.
[70]Kroemer G, Galluzzi L,Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007; 87(1):99-163.
[71]Zhang DW, Shao J, Lin J, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009; 325(5938):332-336.
[72]Festjens N. Vanden Berghe T, Cornelis S, et al. RIP1, a kinase on the crossroads of a cell's decision to live or die. Cell Death Differ 2007; 14(3): 400-410.
[73]Degterev A, Huang Z, Boyce M. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005; 1(2):112-119.
[74]Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009; 137(6):1112-1123.
[75]He S, Wang L, Miao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009; 137(6):1100-1111.
[76]Barker FG,2nd, Davis RL, Chang SM, et al. Necrosis as a prognostic factor in glioblastoma multiforme. Cancer 1996; 77(6):1161-1166.
[77]Brat DJ, Castellano-Sanchez AA, Hunter SB, et al. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res 2004; 64(3): 920-927.
[78]Vakkila J,Lotze MT. Inflammation and necrosis promote tumour growth. Nat Rev Immunol 2004; 4(8):641-648.
[79]Edwards JG, Swinson DE, Jones JL, et al. Tumor necrosis correlates with angiogenesis and is a predictor of poor prognosis in malignant mesothelioma. Chest 2003; 124(5):1916-1923.
[80]Bassi R, Giussani P, Anelli V, et al. HMGB1 as an autocrine stimulus in human T98G glioblastoma cells:role in cell growth and migration. J Neurooncol 2008; 87(1):23-33.
[81]Rong Y, Durden DL, Van Meir EG, et al.'Pseudopalisading' necrosis in glioblastoma:a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 2006; 65(6):529-539.
[82]Xie TX, Aldape KD, Gong W, et al. Aberrant NF-kappaB activity is critical in focal necrosis formation of human glioblastoma by regulation of the expression of tissue factor. Int J Oncol 2008; 33(1):5-15.
[83]Rong Y, Post DE, Pieper RO, et al. PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 2005; 65(4): 1406-1413.
[84]Hockel M,Vaupel P. Tumor hypoxia:definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93(4):266-276.
[85]Ricci MS,Zong WX. Chemotherapeutic approaches for targeting cell death pathways. Oncologist 2006; 11(4):342-357.
[86]Proskuryakov SY,Gabai VL. Mechanisms of tumor cell necrosis. Curr Pharm Des 2010; 16(1):56-68.
[87]Zong WX, Ditsworth D, Bauer DE, et al. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 2004; 18(11):1272-1282.
[88]Ha HC,Snyder SH. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A 1999; 96(24): 13978-13982.
[89]Guerriero JL, Ditsworth D, Fan Y, et al. Chemotherapy induces tumor clearance independent of apoptosis. Cancer Res 2008; 68(23):9595-9600.
[90]Scholz C, Wieder T, Starck L, et al. Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway. Oncogene 2005; 24(11):1904-1913.
[91]Hsieh YJ, Wu CC, Chang CJ, et al. Subcellular localization of Photofrin determines the death phenotype of human epidermoid carcinoma A431 cells triggered by photodynamic therapy:when plasma membranes are the main targets. J Cell Physiol 2003; 194(3):363-375.
[92]Miccoli L, Beurdeley-Thomas A, De Pinieux G, et al. Light-induced photoactivation of hypericin affects the energy metabolism of human glioma cells by inhibiting hexokinase bound to mitochondria. Cancer Res 1998; 58(24):5777-5786.
[93]Fabris C, Valduga G, Miotto G, et al. Photosensitization with zinc (II) phthalocyanine as a switch in the decision between apoptosis and necrosis. Cancer Res 2001; 61 (20):7495-7500.
[94]Han W, Li L, Qiu S, et al. Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther 2007; 6(5):1641-1649.
[95]Raza SM, Fuller GN, Rhee CH, et al. Identification of necrosis-associated genes in glioblastoma by cDNA microarray analysis. Clin Cancer Res 2004; 10(1 Pt 1):212-221.
[2]Chiocca EA. Gene therapy:a primer for neurosurgeons. Neurosurgery 2003; 53(2):364-373; discussion 373.
[3]Germano IM,Binello E. Gene therapy as an adjuvant treatment for malignant gliomas:from bench to bedside. J Neurooncol 2009; 93(1):79-87.
[4]Lefranc F, Facchini V,Kiss R. Proautophagic drugs:a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 2007; 12(12):1395-1403.
[5]Krakstad C,Chekenya M. Survival signalling and apoptosis resistance in glioblastomas:opportunities for targeted therapeutics. Mol Cancer 2010; 9(p: 135.
[6]Raza SM, Lang FF, Aggarwal BB, et al. Necrosis and glioblastoma:a friend or a foe? A review and a hypothesis. Neurosurgery 2002; 51(1):2-12; discussion 12-13.
[7]Hammoud MA, Sawaya R, Shi W, et al. Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J Neurooncol 1996; 27(1): 65-73.
[8]Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme:prognosis, extent of resection, and survival. J Neurosurg 2001; 95(2):190-198.
[9]Hotchkiss RS, Strasser A, McDunn JE, et al. Cell death. N Engl J Med 2009; 361(16):1570-1583.
[10]Klionsky DJ. Autophagy:from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8(11):931-937.
[11]Kroemer G, Galluzzi L, Vandenabeele P, et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009; 16(1):3-11.
[12]Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267(5203):1456-1462.
[13]Reed JC. Drug insight:cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Clin Pract Oncol 2006; 3(7):388-398.
[14]Green DR,Kroemer G. Pharmacological manipulation of cell death:clinical applications in sight? J Clin Invest 2005; 115(10):2610-2617.
[15]Galluzzi L,Kroemer G. Necroptosis:a specialized pathway of programmed necrosis. Cell 2008; 135(7):1161-1163.
[16]Hitomi J, Christofferson DE, Ng A, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 2008; 135(7):1311-1323.
[17]Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009; 137(6):1112-1123.
[18]Zhang DW, Shao J, Lin J, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009; 325(5938):332-336.
[19]He S, Wang L, Miao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009; 137(6):1100-1111.
[20]Sun X, Lee J, Navas T, et al. RIP3, a novel apoptosis-inducing kinase. J Biol Chem 1999; 274(24):16871-16875.
[21]Yu PW, Huang BC, Shen M, et al. Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB. Curr Biol 1999; 9(10):539-542.
[22]Kasof GM, Prosser JC, Liu D, et al. The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria. FEBS Lett 2000; 473(3):285-291.
[23]Newton K, Sun X.Dixit VM. Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol Cell Biol 2004; 24(4):1464-1469.
[24]Reifenberger G,Collins VP. Pathology and molecular genetics of astrocytic gliomas. J Mol Med 2004; 82(10):656-670.
[25]Sonoda Y, Ozawa T, Aldape KD, et al. Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res 2001; 61(18):6674-6678.
[26]Holland EC, Celestino J, Dai C, et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 2000; 25(1):55-57.
[27]Bjornsti MA,Houghton PJ. The TOR pathway:a target for cancer therapy. Nat Rev Cancer 2004; 4(5):335-348.
[28]Gallia GL, Tyler BM, Hann CL, et al. Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther 2009; 8(2): 386-393.
[29]Liu XH, Yu EZ, Li YY, et al. RNA interference targeting Akt promotes apoptosis in hypoxia-exposed human neuroblastoma cells. Brain Res 2006; 1070(1):24-30.
[30]Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987-996.
[31]Newlands ES, Stevens MF, Wedge SR, et al. Temozolomide:a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 1997; 23(1):35-61.
[32]Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10):997-1003.
[33]Marchesi F, Turriziani M, Tortorelli G, et al. Triazene compounds:mechanism of action and related DNA repair systems. Pharmacol Res 2007; 56(4): 275-287.
[34]Villano JL, Seery TE,Bressler LR. Temozolomide in malignant gliomas: current use and future targets. Cancer Chemother Pharmacol 2009; 64(4): 647-655.
[35]Wharton SB, McNelis U, Bell HS, et al. Expression of poly(ADP-ribose) polymerase and distribution of poly(ADP-ribosyl)ation in glioblastoma and in a glioma multicellular tumour spheroid model. Neuropathol Appl Neurobiol 2000; 26(6):528-535.
[36]Barton VN, Donson AM, Kleinschmidt-DeMasters BK, et al. PARP1 expression in pediatric central nervous system tumors. Pediatr Blood Cancer 2009; 53(7):1227-1230.
[37]Virag L,Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 2002; 54(3):375-429.
[38]Miknyoczki S, Chang H, Grobelny J, et al. The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. Mol Cancer Ther 2007; 6(8):2290-2302.
[39]Donawho CK, Luo Y, Penning TD, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 2007; 13(9):2728-2737.
[40]Plummer R, Jones C, Middleton M, et al. Phase Ⅰ study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res 2008; 14(23):7917-7923.
[41]Daniel RA, Rozanska AL, Thomas HD, et al. Inhibition of poly(ADP-ribose) polymerase-1 enhances temozolomide and topotecan activity against childhood neuroblastoma. Clin Cancer Res 2009; 15(4):1241-1249.
[42]Iwami K, Natsume A,Wakabayashi T. Gene therapy for high-grade glioma. Neurol Med Chir (Tokyo) 2010; 50(9):727-736.
[43]Guo SW, Che HM,Li WZ. Anti-tumor effect of lentivirus-mediated gene transfer of alphastatin on Human glioma. Cancer Sci 2011.
[44]Manjunath N, Wu H, Subramanya S, et al. Lentiviral delivery of short hairpin RNAs. Adv Drug Deliv Rev 2009; 61(9):732-745.
[45]Lever AM, Strappe PM,Zhao J. Lentiviral vectors. J Biomed Sci 2004:11(4): 439-449.
[46]Martin-Rendon E, Azzouz M,Mazarakis ND. Lentiviral vectors for the treatment of neurodegenerative diseases. Curr Opin Mol Ther 2001; 3(5): 476-481.
[47]Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003; 348(3):255-256.
[48]Ralph GS, Binley K, Wong LF, et al. Gene therapy for neurodegenerative and ocular diseases using lentiviral vectors. Clin Sci (Lond) 2006; 110(1):37-46.
[49]Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272(5259):263-267.
[50]Wiznerowicz M,Trono D. Harnessing HIV for therapy, basic research and biotechnology. Trends Biotechnol 2005; 23(1):42-47.
[51]Cockrell AS.Kafri T. Gene delivery by lentivirus vectors. Mol Biotechnol 2007; 36(3):184-204.
[52]Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114(2): 97-109.
[53]Stiles B, Gilman V, Khanzenzon N, et al. Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis. Mol Cell Biol 2002; 22(11): 3842-3851.
[54]Kandel ES, Skeen J, Majewski N, et al. Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage. Mol Cell Biol 2002; 22(22):7831-7841.
[55]Riemenschneider MJ, Betensky RA, Pasedag SM, et al. AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling. Cancer Res 2006; 66(11):5618-5623.
[56]Suzuki Y, Shirai K, Oka K, et al. Higher pAkt expression predicts a significant worse prognosis in glioblastomas. J Radiat Res (Tokyo) 2010; 51(3):343-348.
[57]Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007; 21(21): 2683-2710.
[58]Majno G,Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. AmJ Pathol 1995; 146(1):3-15.
[59]Adams JM,Cory S. Bcl-2-regulated apoptosis:mechanism and therapeutic potential. Curr Opin Immunol 2007; 19(5):488-496.
[60]Marsden VS,Strasser A. Control of apoptosis in the immune system:Bcl-2, BH3-only proteins and more. Annu Rev Immunol 2003; 21(71-105.
[61]Golstein P,Kroemer G. Cell death by necrosis:towards a molecular definition. Trends Biochem Sci 2007; 32(1):37-43.
[62]Zong WX,Thompson CB. Necrotic death as a cell fate. Genes Dev 2006; 20(1): 1-15.
[63]Galluzzi L, Kepp O,Kroemer G. RIP kinases initiate programmed necrosis. J Mol Cell Biol 2009:1(1):8-10.
[64]Petersen SL, Wang L, Yalcin-Chin A, et al. Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 2007; 12(5):445-456.
[65]Van Herreweghe F, Festjens N, Declercq W, et al. Tumor necrosis factor-mediated cell death:to break or to burst, that's the question. Cell Mol Life Sci 2010; 67(10):1567-1579.
[66]Mabrouk GM, Ali EM, El-Rehany MA, et al. TGF-betal, TNF-alpha and cytochrome c in human astrocytic tumors:a short-term follow up and correlation with survival. Clin Biochem 2007; 40(3-4):255-260.
[67]Chen QM, Bartholomew JC, Campisi J, et al. Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts:p53 and Rb control G1 arrest but not cell replication. Biochem J 1998; 332 (Pt 1)(43-50.
[68]Irani K, Xia Y, Zweier JL, et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 1997; 275(5306):1649-1652.
[69]Oh SY, Sohn YW, Park JW, et al. Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species mediated damage. Mol Cancer Ther 2007; 6(8):2178-2187.
[70]Brandsma D, Stalpers L, Taal W, et al. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008; 9(5):453-461.
[71]Minniti G, Armosini V, Salvati M, et al. Fractionated stereotactic reirradiation and concurrent temozolomide in patients with recurrent glioblastoma. J Neurooncol 2010.
[72]Lefranc F,Kiss R. Autophagy, the Trojan horse to combat glioblastomas. Neurosurg Focus 2006; 20(4) p:E7.
[73]Baker SD, Wirth M, Statkevich P, et al. Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. Clin Cancer Res 1999; 5(2):309-317.
[74]Kanzawa T, Bedwell J, Kondo Y, et al. Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide. J Neurosurg 2003; 99(6): 1047-1052.
[75]Roos WP, Batista LF, Naumann SC, et al. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 2007; 26(2):186-197.
[76]Takeuchi H, Kondo Y, Fujiwara K, et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 2005; 65(8):3336-3346.
[77]Kanzawa T, Germano IM, Komata T, et al. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 2004; 11(4):448-457.
[78]Tolcher AW, Gerson SL, Denis L, et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 2003; 88(7):1004-1011.
[79]Turriziani M, Caporaso P, Bonmassar L, et al.06-(4-bromothenyl)guanine (PaTrin-2), a novel inhibitor of O6-alkylguanine DNA alkyl-transferase, increases the inhibitory activity of temozolomide against human acute leukaemia cells in vitro. Pharmacol Res 2006; 53(4):317-323.
[80]Rouleau M, Patel A, Hendzel MJ, et al. PARP inhibition:PARP1 and beyond. Nat Rev Cancer 2010; 10(4):293-301.
[81]Burkle A. Physiology and pathophysiology of poly(ADP-ribosyl)ation. Bioessays 2001; 23(9):795-806.
[82]Tomoda T, Kurashige T, Moriki T, et al. Enhanced expression of poly(ADP-ribose) synthetase gene in malignant lymphoma. Am J Hematol 1991; 37(4):223-227.
[83]Shiobara M, Miyazaki M, Ito H, et al. Enhanced polyadenosine diphosphate-ribosylation in cirrhotic liver and carcinoma tissues in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2001; 16(3):338-344.
[84]Fukushima M, Kuzuya K, Ota K, et al. Poly(ADP-ribose) synthesis in human cervical cancer cell-diagnostic cytological usefulness. Cancer Lett 1981; 14(3): 227-236.
[85]Wielckens K, Garbrecht M, Kittler M, et al. ADP-ribosylation of nuclear proteins in normal lymphocytes and in low-grade malignant non-Hodgkin lymphoma cells. Eur J Biochem 1980; 104(1):279-287.
[86]de Murcia JM, Niedergang C, Trucco C, et al. Requirement of poly (ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A 1997; 94(14):7303-7307.
[87]Schreiber V, Ame JC, Dolle P, et al. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 2002; 277(25):23028-23036.
[1]Wen PY,Kesari S. Malignant gliomas in adults. N Engl J Med 2008; 359(5): 492-507.
[2]Lefranc F, Facchini V,Kiss R. Proautophagic drugs:a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 2007; 12(12):1395-1403.
[3]Krakstad C,Chekenya M. Survival signalling and apoptosis resistance in glioblastomas:opportunities for targeted therapeutics. Mol Cancer 2010; 9(p: 135.
[4]Raza SM, Lang FF, Aggarwal BB, et al. Necrosis and glioblastoma:a friend or a foe? A review and a hypothesis. Neurosurgery 2002; 51(1):2-12; discussion 12-13.
[5]Hammoud MA, Sawaya R, Shi WM, et al. Prognostic significance of preoperative MRI scans in glioblastoma multiforme. Journal of Neuro-Oncology 1996; 27(1):65-73.
[6]Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme:prognosis, extent of resection, and survival. J Neurosurg 2001; 95(2):190-198.
[7]Jensen RL. Brain tumor hypoxia:tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol 2009; 92(3): 317-335.
[8]Hotchkiss RS, Strasser A, McDunn JE, et al. Cell death. N Engl J Med 2009; 361(16):1570-1583.
[9]Klionsky DJ. Autophagy:from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8(11):931-937.
[10]Kroemer G,Jaattela M. Lysosomes and autophagy in cell death control. Nat Rev Cancer 2005; 5(11):886-897.
[11]Levine B,Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol 2007; 7(10):767-777.
[12]Kroemer G, Galluzzi L, Vandenabeele P, et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009; 16(1):3-11.
[13]Majno G,Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 1995; 146(1):3-15.
[14]Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267(5203):1456-1462.
[15]Reed JC. Drug insight:cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Clin Pract Oncol 2006; 3(7):388-398.
[16]Green DR,Kroemer G. Pharmacological manipulation of cell death:clinical applications in sight? J Clin Invest 2005; 115(10):2610-2617.
[17]Hitomi J, Christofferson DE, Ng A, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 2008; 135(7):1311-1323.
[18]Zong WX,Thompson CB. Necrotic death as a cell fate. Genes Dev 2006; 20(1): 1-15.
[19]Galluzzi L, Aaronson SA, Abrams J, et al. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ 2009; 16(8):1093-1107.
[20]Festjens N, Vanden Berghe T,Vandenabeele P. Necrosis, a well-orchestrated form of cell demise:signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 2006; 1757(9-10):1371-1387.
[21]Kerr JF, Wyllie AH,Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26(4): 239-257.
[22]Adams JM,Cory S. Bcl-2-regulated apoptosis:mechanism and therapeutic potential. Curr Opin Immunol 2007; 19(5):488-496.
[23]Marsden VS,Strasser A. Control of apoptosis in the immune system:Bcl-2, BH3-only proteins and more. Annu Rev Immunol 2003; 21(71-105.
[24]Golstein P,Kroemer G. Cell death by necrosis:towards a molecular definition. Trends Biochem Sci 2007; 32(1):37-43.
[25]Yuan J, Shaham S, Ledoux S, et al. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 1993; 75(4):641-652.
[26]Salmena L, Lemmers B, Hakem A, et al. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev 2003; 17(7):883-895.
[27]Green DR. Apoptotic pathways:ten minutes to dead. Cell 2005; 121(5): 671-674.
[28]Newton K, Harris AW. Bath ML. et al. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J 1998; 17(3):706-718.
[29]Yu JW,Shi Y. FLIP and the death effector domain family. Oncogene 2008; 27(48):6216-6227.
[30]Wang X. The expanding role of mitochondria in apoptosis. Genes Dev 2001; 15(22):2922-2933.
[31]Strasser A. The role of BH3-only proteins in the immune system. Nat Rev Immunol 2005; 5(3):189-200.
[32]Goldstein JC, Munoz-Pinedo C, Ricci JE, et al. Cytochrome c is released in a single step during apoptosis. Cell Death Differ 2005; 12(5):453-462.
[33]Hughes PD, Belz GT, Fortner KA, et al. Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Immunity 2008; 28(2):197-205.
[34]Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007; 21(21): 2683-2710.
[35]Weller M, Malipiero U, Aguzzi A, et al. Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. J Clin Invest 1995; 95(6):2633-2643.
[36]Roth W, Isenmann S, Naumann U, et al. Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem Biophys Res Commun 1999; 265(2): 479-483.
[37]Nagane M, Pan G, Weddle JJ, et al. Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 2000; 60(4):847-853.
[38]Rohn TA, Wagenknecht B, Roth W, et al. CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. Oncogene 2001; 20(31): 4128-4137.
[39]Roth W, Isenmann S, Nakamura M, et al. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Res 2001; 61(6):2759-2765.
[40]Kuijlen JM, Mooij JJ, Platteel I, et al. TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme. J Neurooncol 2006; 78(2):161-171.
[41]Fulda S, Wick W, Weller M, et al. Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 2002; 8(8):808-815.
[42]Green DR,Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305(5684):626-629.
[43]Krajewski S, Krajewska M, Ehrmann J, et al. Immunohistochemical analysis of Bcl-2, Bcl-X, Mcl-1, and Bax in tumors of central and peripheral nervous system origin. Am J Pathol 1997; 150(3):805-814.
[44]Strik H, Deininger M, Streffer J, et al. BCL-2 family protein expression in initial and recurrent glioblastomas:modulation by radiochemotherapy. J Neurol Neurosurg Psychiatry 1999; 67(6):763-768.
[45]Ruano Y, Mollejo M, Camacho FI, et al. Identification of survival-related genes of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma multiforme. Cancer 2008; 112(7):1575-1584.
[46]Wick W, Wagner S, Kerkau S, et al. BCL-2 promotes migration and invasiveness of human glioma cells. FEBS Lett 1998; 440(3):419-424.
[47]Stegh AH, Kim H, Bachoo RM, et al. Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma. Genes Dev 2007; 21(1):98-111.
[48]Stegh AH, Kesari S, Mahoney JE. et al. Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma. Proc Natl Acad Sci U S A 2008; 105(31):10703-10708.
[49]Ashford TP,Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol 1962; 12(198-202.
[50]Watanabe E, Muenzer JT. Hawkins WG, et al. Sepsis induces extensive autophagic vacuolization in hepatocytes:a clinical and laboratory-based study. Lab Invest 2009; 89(5):549-561.
[51]Espert L, Denizot M, Grimaldi M, et al. Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J Clin Invest 2006; 116(8):2161-2172.
[52]Levine B,Yuan J. Autophagy in cell death:an innocent convict? J Clin Invest 2005; 115(10):2679-2688.
[53]Galluzzi L, Maiuri MC, Vitale I, et al. Cell death modalities:classification and pathophysiological implications. Cell Death Differ 2007; 14(7):1237-1243.
[54]Amaravadi RK,Thompson CB. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res 2007; 13(24):7271-7279.
[55]Marx J. Autophagy:is it cancer's friend or foe? Science 2006; 312(5777): 1160-1161.
[56]Maiuri MC, Tasdemir E, Criollo A, et al. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ 2009; 16(1):87-93.
[57]Takahashi Y, Coppola D, Matsushita N, et al. Bif-1 interacts with Beelin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007; 9(10):1142-1151.
[58]Ahn CH, Jeong EG, Lee JW, et al. Expression of beclin-1, an autophagy-related protein, in gastric and colorectal cancers. APMIS 2007; 115(12):1344-1349.
[59]Liang C, Feng P, Ku B, et al. Autophagic and tumour suppressor activity of a novel Beclinl-binding protein UVRAG. Nat Cell Biol 2006; 8(7):688-699.
[60]Desai BN, Myers BR,Schreiber SL. FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc Natl Acad Sci U S A 2002; 99(7):4319-4324.
[61]Takeuchi H, Kondo Y, Fujiwara K, et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 2005; 65(8):3336-3346.
[62]Eshleman JS, Carlson BL. Mladek AC, et al. Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 2002; 62(24):7291-7297.
[63]Takeuchi H, Kanzawa T, Kondo Y, et al. Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells. Br J Cancer 2004; 90(5):1069-1075.
[64]Lefranc F, Brotchi J,Kiss R. Possible future issues in the treatment of glioblastomas:special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 2005; 23(10): 2411-2422.
[65]Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987-996.
[66]Kanzawa T, Germano IM, Komata T, et al. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 2004; 11(4):448-457.
[67]Kanzawa T, Bedwell J, Kondo Y, et al. Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide. J Neurosurg 2003; 99(6): 1047-1052.
[68]Galluzzi L,Kroemer G. Necroptosis:a specialized pathway of programmed necrosis. Cell 2008; 135(7):1161-1163.
[69]Nicotera P,Melino G. Regulation of the apoptosis-necrosis switch. Oncogene 2004; 23(16):2757-2765.
[70]Kroemer G, Galluzzi L,Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007; 87(1):99-163.
[71]Zhang DW, Shao J, Lin J, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009; 325(5938):332-336.
[72]Festjens N. Vanden Berghe T, Cornelis S, et al. RIP1, a kinase on the crossroads of a cell's decision to live or die. Cell Death Differ 2007; 14(3): 400-410.
[73]Degterev A, Huang Z, Boyce M. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005; 1(2):112-119.
[74]Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009; 137(6):1112-1123.
[75]He S, Wang L, Miao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009; 137(6):1100-1111.
[76]Barker FG,2nd, Davis RL, Chang SM, et al. Necrosis as a prognostic factor in glioblastoma multiforme. Cancer 1996; 77(6):1161-1166.
[77]Brat DJ, Castellano-Sanchez AA, Hunter SB, et al. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res 2004; 64(3): 920-927.
[78]Vakkila J,Lotze MT. Inflammation and necrosis promote tumour growth. Nat Rev Immunol 2004; 4(8):641-648.
[79]Edwards JG, Swinson DE, Jones JL, et al. Tumor necrosis correlates with angiogenesis and is a predictor of poor prognosis in malignant mesothelioma. Chest 2003; 124(5):1916-1923.
[80]Bassi R, Giussani P, Anelli V, et al. HMGB1 as an autocrine stimulus in human T98G glioblastoma cells:role in cell growth and migration. J Neurooncol 2008; 87(1):23-33.
[81]Rong Y, Durden DL, Van Meir EG, et al.'Pseudopalisading' necrosis in glioblastoma:a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 2006; 65(6):529-539.
[82]Xie TX, Aldape KD, Gong W, et al. Aberrant NF-kappaB activity is critical in focal necrosis formation of human glioblastoma by regulation of the expression of tissue factor. Int J Oncol 2008; 33(1):5-15.
[83]Rong Y, Post DE, Pieper RO, et al. PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 2005; 65(4): 1406-1413.
[84]Hockel M,Vaupel P. Tumor hypoxia:definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93(4):266-276.
[85]Ricci MS,Zong WX. Chemotherapeutic approaches for targeting cell death pathways. Oncologist 2006; 11(4):342-357.
[86]Proskuryakov SY,Gabai VL. Mechanisms of tumor cell necrosis. Curr Pharm Des 2010; 16(1):56-68.
[87]Zong WX, Ditsworth D, Bauer DE, et al. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 2004; 18(11):1272-1282.
[88]Ha HC,Snyder SH. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A 1999; 96(24): 13978-13982.
[89]Guerriero JL, Ditsworth D, Fan Y, et al. Chemotherapy induces tumor clearance independent of apoptosis. Cancer Res 2008; 68(23):9595-9600.
[90]Scholz C, Wieder T, Starck L, et al. Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway. Oncogene 2005; 24(11):1904-1913.
[91]Hsieh YJ, Wu CC, Chang CJ, et al. Subcellular localization of Photofrin determines the death phenotype of human epidermoid carcinoma A431 cells triggered by photodynamic therapy:when plasma membranes are the main targets. J Cell Physiol 2003; 194(3):363-375.
[92]Miccoli L, Beurdeley-Thomas A, De Pinieux G, et al. Light-induced photoactivation of hypericin affects the energy metabolism of human glioma cells by inhibiting hexokinase bound to mitochondria. Cancer Res 1998; 58(24):5777-5786.
[93]Fabris C, Valduga G, Miotto G, et al. Photosensitization with zinc (II) phthalocyanine as a switch in the decision between apoptosis and necrosis. Cancer Res 2001; 61 (20):7495-7500.
[94]Han W, Li L, Qiu S, et al. Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther 2007; 6(5):1641-1649.
[95]Raza SM, Fuller GN, Rhee CH, et al. Identification of necrosis-associated genes in glioblastoma by cDNA microarray analysis. Clin Cancer Res 2004; 10(1 Pt 1):212-221.