细胞程序性坏死的研究进展_West China Medical Journal

Authors：

 陈鹏亮 ¹ , 郭进明 ¹ , 赖文杰 ¹ , 李飞 ¹ ,  刘明 ²

1. ;
2. ;

Corresponding author：

刘明, Email: 27594397@qq.com

Keywords：

细胞死亡; 程序性坏死; 调控机制

DOI：

10.7507/1002-0179.201600394

Video：

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Abstract Full text Figures/Tables Video References Cited by

坏死是细胞死亡的3种表现形式之一，一直是生命科学的研究热点和难点。越来越多的研究发现坏死可被调节，并参与了许多疾病的病理生理过程。该文对目前研究涉及的有关细胞程序性坏死的特点、分子机制和病理生理特点加以综述。将来对其体内具体分子级联反应过程和分子级联反应过程的揭示，有利于更好地认识细胞生命过程，拓展包括肿瘤治疗在内的生命科学研究新领域。

Citation： 陈鹏亮, 郭进明, 赖文杰, 李飞, 刘明. 细胞程序性坏死的研究进展. West China Medical Journal, 2016, 31(8): 1447-1452. doi: 10.7507/1002-0179.201600394 Copy

1.	Kerr JF, Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics[J]. Br J Cancer, 1972, 26(4):239-257.
2.	Kiraz Y, Adan A, Kartal YM, et al. Major apoptotic mechanisms and genes involved in apoptosis[J]. Tumor Biol, 2016, 37(4):4235-4251.
3.	Fuchs Y, Steller H. Programmed cell death in animal development and disease[J]. Cell, 2011, 147(4):742-758.
4.	Kroemer G, El-Deiry WS, Golstein P, et al. Classification of cell death:recommendations of the nomenclature committee on cell death[J]. Cell Death Differ, 2005, 12(Suppl 2):1463-1467.
5.	Goossens V, Grooten J, De Vos K, et al. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity[J]. Proc Natl Acad Sci USA, 1995, 92(18):8115-8159.
6.	Hirsch T, Marchetti P, Susin S, et al. The apoptosis-necrosis paradox.Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death[J]. Oncogene, 1997, 15(13):1573-1581.
7.	Holler N, Zaru R, Micheau O, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule[J]. Nat Immunol, 2000, 1(6):489-495.
8.	Degterev A, Huang ZH, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury[J]. Nat Chem Biol, 2005, 1(2):112-119.
9.	Kroemer G, Galluzzi L, Vandenabeele P, et al. Classification of cell death:recommendations of the nomenclature committee on cell death 2009[J]. Cell Death Differ, 2009, 16(1):3-11.
10.	Vercammen D, Brouckaert G, Denecker G, et al. Dual signaling of the Fas receptor:initiation of both apoptotic and necrotic cell death pathways[J]. J Exp Med, 1998, 188(5):919-930.
11.	Laster SM, Wood JG, Gooding LR. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis[J]. J Immunol, 1988, 141(8):2629-2634.
12.	Vercammen D, Beyaert R, Denecker G, et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor[J]. J Exp Med, 1998, 187(9):1477-1485.
13.	Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes[J]. Cell, 2003, 114(2):181-190.
14.	Hacker H, Karin M. Regulation and function of IKK and IKK-related kinases[J]. Sci STKE, 2006(357):re13.
15.	Csomos RA, Brady GF, Duckett CS. Enhanced cytoprotective effects of the inhibitor of apoptosis protein cellular IAP1 through stabilization with TRAF2[J]. J Biol Chem, 2009, 284(31):20531-20539.
16.	Bertrand MJ, Milutinovic S, Dickson KM, et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination[J]. Mol Cell, 2008, 30(6):689-700.
17.	Alvarez SE, Harikumar KB, Hait NC, et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2[J]. Nature, 2010, 465(7301):1084-1088.
18.	Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation[J]. Cell, 2009, 137(6):1112-1123.
19.	He S, Wang L, Miao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha[J]. Cell, 2009, 137(6):1100-1111.
20.	O'donnell MA, Legarda-Addison D, Skountzos P, et al. Ubiquitination of RIP1 regulates an NF-kappa B Independent cell-death Switch in TNF signaling[J]. Current Biology, 2007, 17(5):418-424.
21.	Ting AT, Pimentel-Muinos FX, Seed B. RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis[J]. EMBO J, 1996, 15(22):6189-6196.
22.	Hitomi J, Christofferson DE, Ng A, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway[J]. Cell, 2008, 135(7):1311-1323.
23.	Shembade N, Ma A, Harhaj EW. Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes[J]. Science, 2010, 327(5969):1135-1139.
24.	Enesa K, Zakkar M, Chaudhury H, et al. NF-kappaB suppression by the deubiquitinating enzyme cezanne:a novel negative feedback loop in pro-inflammatory signaling[J]. J Biol Chem, 2008, 283(11):7036-7045.
25.	Xu XS, Chua CC, Zhang M, et al. The role of PARP activation in glutamate-induced necroptosis in HT-22 cells[J]. Brain Res, 2010(1343):206-212.
26.	Feng SS, Yang YH, Mei YD, et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain[J]. Cell Signal, 2007, 19(10):2056-2067.
27.	Lin Y, Devin A, Rodriguez Y, et al. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis[J]. Genes Dev, 1999, 13(19):2514-2526.
28.	Osborn SL, Diehl G, Han SJ, et al. Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis[J]. Proc Natl Acad Sci USA, 2010, 107(29):13034-13039.
29.	Lin Y, Choksi S, Shen HM, et al. Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation[J]. J Biol Chem, 2004, 279(11):10822-10828.
30.	Declercq W, Vanden Berghe T, Vandenabeele P. RIP kinases at the crossroads of cell death and survival[J]. Cell, 2009, 138(2):229-232.
31.	Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways[J]. Cell, 2008, 133(4):693-703.
32.	Zhang DW, Shao J, Lin J, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis[J]. Science, 2009, 325(5938):332-336.
33.	Sun XQ, Yin JP, Starovasnik MA, et al. Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3[J]. J Biol Chem, 2002, 277(11):9505-9511.
34.	Upton JW, Kaiser WJ, Mocarski ES. Virus inhibition of RIP3-dependent necrosis[J]. Cell Host Microbe, 2010, 7(4):302-313.
35.	Zhang DW, Zheng M, Zhao J, et al. Multiple death pathways in TNF-treated fibroblasts:RIP3-and RIP1-dependent and Independent routes[J]. Cell Res, 2011, 21(2):368-371.
36.	Sun L, Wang H, Wang Z, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase[J]. Cell, 2012, 148(1/2):213-227.
37.	Zhao J, Jitkaew S, Cai ZY, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis[J]. Proc Natl Acad Sci USA, 2012, 109(14):5322-5327.
38.	Mates JM, Segura JA, Campos-Sandoval JA, et al. Glutamine homeostasis and mitochondrial dynamics[J]. Int J Biochem Cell Biol, 2009, 41(10):2051-2061.
39.	Albrecht J, Norenberg MD. Glutamine:a Trojan horse in ammonia neurotoxicity[J]. Hepatology, 2006, 44(4):788-794.
40.	Van Herreweghe F, Mao J, Chaplen FW, et al. Tumor necrosis factor-induced modulation of glyoxalase I activities through phosphorylation by PKA results in cell death and is accompanied by the formation of a specific methylglyoxal-derived AGE[J]. Proc Natl Acad Sci U S A, 2002, 99(2):949-954.
41.	Kim YS, Morgan MJ, Choksi S, et al. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death[J]. Mol Cell, 2007, 26(5):675-687.
42.	Chen TY, Chi IH, Wang JS, et al. Reactive Oxygen species are involved in FasL-induced caspase-independent cell death and inflammatory responses[J]. Free Radical Biol Med, 2009, 46(5):643-655.
43.	Thon L, Mohlig H, Mathieu S, et al. Ceramide mediates caspase-independent programmed cell death[J]. FASEB J, 2005, 19(14):1945-1956.
44.	Vanden Berghe T, Vanlangenakker N, Parthoens E, et al. Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features[J]. Cell Death Differ, 2010, 17(6):922-930.
45.	Wu YT, Tan HL, Huang Q, et al. zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFalpha mediated by the PKC-MAPKs-AP-1 pathway[J]. Cell Death Differ, 2011, 18(1):26-37.
46.	Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death[J]. Physiol Rev, 2007, 87(1):99-163.
47.	Baines CP, Kaiser RA, Sheiko TA, et al. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death[J]. Nat Cell Biol, 2007, 9(5):550-555.
48.	Boya P, Kroemer G. Beclin 1:a BH3-only protein that fails to induce apoptosis[J]. Oncogene, 2009, 28(21):2125-2127.
49.	Galluzzi L, Blomgren K, Kroemer G. Mitochondrial membrane permeabilization in neuronal injury[J]. Nat Rev Neurosci, 2009, 10(7):481-494.
50.	Boya P, Andreau K, Poncet D, et al. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion[J]. J Exp Med, 2003, 197(10):1323-1334.
51.	Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control[J]. Nat Rev Cancer, 2005, 5(11):886-897.
52.	Bano D, Young KW, Guerin CJ, et al. Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity[J]. Cell, 2005, 120(2):275-285.
53.	Tang D, Kang R, Xiao W, et al. Nuclear heat shock protein 72 as a negative regulator of oxidative stress (hydrogen peroxide)-induced HMGB1 cytoplasmic translocation and release[J]. J Immunol, 2007, 178(11):7376-7384.
54.	Bonventre JV, Huang Z, Taheri MR, et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2[J]. Nature, 1997, 390(6660):622-625.
55.	Mota RA, Sanchez-Bueno F, Saenz L, et al. Inhibition of poly (ADP-ribose) polymerase attenuates the severity of acute pancreatitis and associated lung injury[J]. Lab Invest, 2005, 85(10):1250-1262.
56.	Maxwell SA, Mousavi-Fard S. Non-Hodgkin's B-cell lymphoma:advances in molecular strategies targeting drug resistance[J]. Exp Biol Med, 2013, 238(9):971-990.
57.	Kęsy J, Januszkiewicz-Lewandowska D. Genes and childhood leukemia[J]. Postepy Hig Med Dosw (Online), 2015(69):302-308.
58.	Han W, Li L, Qiu S, et al. Shikonin circumvents cancer drug resistance by induction of a necroptotic death[J]. Mol Cancer Ther, 2007, 6(5):1641-1649.

1. Kerr JF, Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics[J]. Br J Cancer, 1972, 26(4):239-257.
2. Kiraz Y, Adan A, Kartal YM, et al. Major apoptotic mechanisms and genes involved in apoptosis[J]. Tumor Biol, 2016, 37(4):4235-4251.
3. Fuchs Y, Steller H. Programmed cell death in animal development and disease[J]. Cell, 2011, 147(4):742-758.
4. Kroemer G, El-Deiry WS, Golstein P, et al. Classification of cell death:recommendations of the nomenclature committee on cell death[J]. Cell Death Differ, 2005, 12(Suppl 2):1463-1467.
5. Goossens V, Grooten J, De Vos K, et al. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity[J]. Proc Natl Acad Sci USA, 1995, 92(18):8115-8159.
6. Hirsch T, Marchetti P, Susin S, et al. The apoptosis-necrosis paradox.Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death[J]. Oncogene, 1997, 15(13):1573-1581.
7. Holler N, Zaru R, Micheau O, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule[J]. Nat Immunol, 2000, 1(6):489-495.
8. Degterev A, Huang ZH, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury[J]. Nat Chem Biol, 2005, 1(2):112-119.
9. Kroemer G, Galluzzi L, Vandenabeele P, et al. Classification of cell death:recommendations of the nomenclature committee on cell death 2009[J]. Cell Death Differ, 2009, 16(1):3-11.
10. Vercammen D, Brouckaert G, Denecker G, et al. Dual signaling of the Fas receptor:initiation of both apoptotic and necrotic cell death pathways[J]. J Exp Med, 1998, 188(5):919-930.
11. Laster SM, Wood JG, Gooding LR. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis[J]. J Immunol, 1988, 141(8):2629-2634.
12. Vercammen D, Beyaert R, Denecker G, et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor[J]. J Exp Med, 1998, 187(9):1477-1485.
13. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes[J]. Cell, 2003, 114(2):181-190.
14. Hacker H, Karin M. Regulation and function of IKK and IKK-related kinases[J]. Sci STKE, 2006(357):re13.
15. Csomos RA, Brady GF, Duckett CS. Enhanced cytoprotective effects of the inhibitor of apoptosis protein cellular IAP1 through stabilization with TRAF2[J]. J Biol Chem, 2009, 284(31):20531-20539.
16. Bertrand MJ, Milutinovic S, Dickson KM, et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination[J]. Mol Cell, 2008, 30(6):689-700.
17. Alvarez SE, Harikumar KB, Hait NC, et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2[J]. Nature, 2010, 465(7301):1084-1088.
18. Cho YS, Challa S, Moquin D, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation[J]. Cell, 2009, 137(6):1112-1123.
19. He S, Wang L, Miao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha[J]. Cell, 2009, 137(6):1100-1111.
20. O'donnell MA, Legarda-Addison D, Skountzos P, et al. Ubiquitination of RIP1 regulates an NF-kappa B Independent cell-death Switch in TNF signaling[J]. Current Biology, 2007, 17(5):418-424.
21. Ting AT, Pimentel-Muinos FX, Seed B. RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis[J]. EMBO J, 1996, 15(22):6189-6196.
22. Hitomi J, Christofferson DE, Ng A, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway[J]. Cell, 2008, 135(7):1311-1323.
23. Shembade N, Ma A, Harhaj EW. Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes[J]. Science, 2010, 327(5969):1135-1139.
24. Enesa K, Zakkar M, Chaudhury H, et al. NF-kappaB suppression by the deubiquitinating enzyme cezanne:a novel negative feedback loop in pro-inflammatory signaling[J]. J Biol Chem, 2008, 283(11):7036-7045.
25. Xu XS, Chua CC, Zhang M, et al. The role of PARP activation in glutamate-induced necroptosis in HT-22 cells[J]. Brain Res, 2010(1343):206-212.
26. Feng SS, Yang YH, Mei YD, et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain[J]. Cell Signal, 2007, 19(10):2056-2067.
27. Lin Y, Devin A, Rodriguez Y, et al. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis[J]. Genes Dev, 1999, 13(19):2514-2526.
28. Osborn SL, Diehl G, Han SJ, et al. Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis[J]. Proc Natl Acad Sci USA, 2010, 107(29):13034-13039.
29. Lin Y, Choksi S, Shen HM, et al. Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation[J]. J Biol Chem, 2004, 279(11):10822-10828.
30. Declercq W, Vanden Berghe T, Vandenabeele P. RIP kinases at the crossroads of cell death and survival[J]. Cell, 2009, 138(2):229-232.
31. Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways[J]. Cell, 2008, 133(4):693-703.
32. Zhang DW, Shao J, Lin J, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis[J]. Science, 2009, 325(5938):332-336.
33. Sun XQ, Yin JP, Starovasnik MA, et al. Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3[J]. J Biol Chem, 2002, 277(11):9505-9511.
34. Upton JW, Kaiser WJ, Mocarski ES. Virus inhibition of RIP3-dependent necrosis[J]. Cell Host Microbe, 2010, 7(4):302-313.
35. Zhang DW, Zheng M, Zhao J, et al. Multiple death pathways in TNF-treated fibroblasts:RIP3-and RIP1-dependent and Independent routes[J]. Cell Res, 2011, 21(2):368-371.
36. Sun L, Wang H, Wang Z, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase[J]. Cell, 2012, 148(1/2):213-227.
37. Zhao J, Jitkaew S, Cai ZY, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis[J]. Proc Natl Acad Sci USA, 2012, 109(14):5322-5327.
38. Mates JM, Segura JA, Campos-Sandoval JA, et al. Glutamine homeostasis and mitochondrial dynamics[J]. Int J Biochem Cell Biol, 2009, 41(10):2051-2061.
39. Albrecht J, Norenberg MD. Glutamine:a Trojan horse in ammonia neurotoxicity[J]. Hepatology, 2006, 44(4):788-794.
40. Van Herreweghe F, Mao J, Chaplen FW, et al. Tumor necrosis factor-induced modulation of glyoxalase I activities through phosphorylation by PKA results in cell death and is accompanied by the formation of a specific methylglyoxal-derived AGE[J]. Proc Natl Acad Sci U S A, 2002, 99(2):949-954.
41. Kim YS, Morgan MJ, Choksi S, et al. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death[J]. Mol Cell, 2007, 26(5):675-687.
42. Chen TY, Chi IH, Wang JS, et al. Reactive Oxygen species are involved in FasL-induced caspase-independent cell death and inflammatory responses[J]. Free Radical Biol Med, 2009, 46(5):643-655.
43. Thon L, Mohlig H, Mathieu S, et al. Ceramide mediates caspase-independent programmed cell death[J]. FASEB J, 2005, 19(14):1945-1956.
44. Vanden Berghe T, Vanlangenakker N, Parthoens E, et al. Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features[J]. Cell Death Differ, 2010, 17(6):922-930.
45. Wu YT, Tan HL, Huang Q, et al. zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFalpha mediated by the PKC-MAPKs-AP-1 pathway[J]. Cell Death Differ, 2011, 18(1):26-37.
46. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death[J]. Physiol Rev, 2007, 87(1):99-163.
47. Baines CP, Kaiser RA, Sheiko TA, et al. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death[J]. Nat Cell Biol, 2007, 9(5):550-555.
48. Boya P, Kroemer G. Beclin 1:a BH3-only protein that fails to induce apoptosis[J]. Oncogene, 2009, 28(21):2125-2127.
49. Galluzzi L, Blomgren K, Kroemer G. Mitochondrial membrane permeabilization in neuronal injury[J]. Nat Rev Neurosci, 2009, 10(7):481-494.
50. Boya P, Andreau K, Poncet D, et al. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion[J]. J Exp Med, 2003, 197(10):1323-1334.
51. Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control[J]. Nat Rev Cancer, 2005, 5(11):886-897.
52. Bano D, Young KW, Guerin CJ, et al. Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity[J]. Cell, 2005, 120(2):275-285.
53. Tang D, Kang R, Xiao W, et al. Nuclear heat shock protein 72 as a negative regulator of oxidative stress (hydrogen peroxide)-induced HMGB1 cytoplasmic translocation and release[J]. J Immunol, 2007, 178(11):7376-7384.
54. Bonventre JV, Huang Z, Taheri MR, et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2[J]. Nature, 1997, 390(6660):622-625.
55. Mota RA, Sanchez-Bueno F, Saenz L, et al. Inhibition of poly (ADP-ribose) polymerase attenuates the severity of acute pancreatitis and associated lung injury[J]. Lab Invest, 2005, 85(10):1250-1262.
56. Maxwell SA, Mousavi-Fard S. Non-Hodgkin's B-cell lymphoma:advances in molecular strategies targeting drug resistance[J]. Exp Biol Med, 2013, 238(9):971-990.
57. Kęsy J, Januszkiewicz-Lewandowska D. Genes and childhood leukemia[J]. Postepy Hig Med Dosw (Online), 2015(69):302-308.
58. Han W, Li L, Qiu S, et al. Shikonin circumvents cancer drug resistance by induction of a necroptotic death[J]. Mol Cancer Ther, 2007, 6(5):1641-1649.

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细胞程序性坏死的研究进展

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