H0-1在维持人骨肉瘤细胞对三氧化二砷抗性中的作用及分子机制研究
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摘要
目的：探讨HO-1在维持人骨肉瘤细胞对三氧化二砷(ATO)抗性中的作用及分子机制。
方法：利用实时定量PCR及Western blot检测ATO对人骨肉瘤MG63及U2OS细胞HO-1诱导的表达；利用shRNA介导的RNA干扰技术阻断ATO对MG63及U2OS细胞中HO-1的诱导，研究其对细胞存活、凋亡、活性氧及对ATO敏感性等生物学行为的影响；应用免疫组织化学染色及Western blot等技术探讨ATO诱导HO-1表达的分子机制。
结果：首先，发现ATO特异性诱导了人骨肉瘤MG63及U2OS细胞HO-1的高度表达；然后，阻断HO-1的诱导后发现能够显著降低细胞对ATO的抗性，表现为明显降低细胞存活率，表现为细胞的凋亡明显增加，而与凋亡密切相关的细胞内ROS累积增多继而增加细胞对ATO的敏感性；另外，发现ATO上调HO-1的表达是通过增加转录因子Nrf2的入核，促进其在核中的转录活性进而调控下游靶基因HO-1的转录水平而发挥作用的。
结论：ATO特异性高幅度诱导了人骨肉瘤细胞HO-1的表达，阻断HO-1的诱导能够显著增加其对化疗药物ATO的敏感性。ATO诱导HO-1表达的分子机制是通过增加转录因子在细胞核中的转录活性，进而调控下游靶蛋白HO-1的表达来发挥作用的。HO-1在维持人骨肉瘤细胞对化疗药物ATO抗性中具有重要的作用，表现为通过清除肿瘤细胞内活性氧的累积继而抑制细胞的凋亡，从而促进细胞对ATO的耐药性。研究结果为研究骨肉瘤的生物学行为及分子机制提供了新的思路，为靶向HO-1的基因治疗配合药物化疗提供了理论依据。
1Highly induction of HO-1by ATO occurs specifically in human osteosarcomaMG63and U2OS cells
Arsenic trioxide (ATO) has been successfully used to treat leukemia and some solidmalignant tumors. But the effect to mesenchymal-derived human osteosarcoma cells andrelevant mechanism are unclear. From the toxic effects of arsenic trioxide on normalcells, oxidative damage plays a major role, so we first test changes of antioxidantgenes in human osteosarcoma MG63and U2OS cells under the induction of arsenictrioxide. Objective: To detect changes of antioxidant genes in human osteosarcomaMG63and U2OS cells which were treated with chemotherapy drugs arsenic trioxide.Methods: We used real-time PCR and Western blot methods to detect the mRNA andprotein expression of several kinds of antioxidant related genes after treatment witharsenic trioxide for24h. Results: HO-1mRNA was increased to more than80and120folds in human osteosarcoma MG63and U2OS cells respectively (P<0.01), whileother detected antioxidant genes changed little (P>0.05). HO-1protein was increasedto more than6and8folds in human osteosarcoma MG63and U2OS cellscorrespondingly (P<0.01). HO-1mRNA was increased to less than8folds and HO-1protein was increased to less than2folds in HUVECs after exposure to ATO.Conclusions: HO-1was highly induced in human osteosarcoma cells upon treatmentof ATO specifically.
2MG63and U2OS cells were transfected with shRNA-based vectors and stablesilenced cellclones were established
ATO could induce HO-1of human osteosarcoma cells highly expressspecifically. Since HO-1could remove reactive oxygen species (ROS) directly, andROS played an important role in apoptosis, we speculated that HO-1was contactedwith the resistance of osteosarcoma cells of arsenic trioxide. Objective: To clarify therole of gene HO-1in chemotherapy of osteosarcoma cells for arsenic trioxide, wedesigned and synthesized short hairpin based plasmid targeting gene of HO-1. Methods: We transfected the shRNA-mediated plasmid and scramble plasmid to MG63andU2OS cells by lipofectin transfection techniques. We got several single cell clonesthrough the resistance of G418and expression of red fluorescent protein. Results andconclusions: The stable silenced cell clones were established by shRNA-mediatedinterference.
3HO-1silencing enhanced ATO-mediated cell death in MG63and U2OSosteosarcoma cells
Objective: To investigate the role of HO-1in susceptibility of humanosteosarcoma cells to arsenic trioxide. To detect if there is any difference inHO-1-shRNA, scramble and parent cell groups, in order to study the pathogenesis ofosteosarcoma with multidrug-resistance and look for effective therapeutic measures.Methods: We analyzed the expression of gene HO-1in MG63and U2OS cells byreal-time PCR and Western blot after transfection. We used CellTiter-Glo assay todetect cell activity and IC50values of arsenic trioxide, and used AnnexinV-FITC/7-AAD and TUNEL assay to detect apoptotic cells, and determinedintracellular accumulation of reactive oxygen species with the ROS detection kit.Results: HO-1was silenced mainly in human osteosarcoma cells in spite of treatmentupon arsenic trioxide. Compared with parent and scramble groups, the apoptosis rateand intracellular accumulation of reactive oxygen species in HO-1silenced cellsincreased significantly in a dose-dependent and time-response effect (P<0.05). TheIC50values of HO-1-shRNA cells to arsenic trioxide were lower than parent andscramble cells (P<0.05). Conclusions: The resistance to arsenic trioxide of humanosteosarcoma MG63and U2OS cells was closely associated with the expression ofHO-1. Silencing HO-1increased the sensitivity of human osteosarcoma MG63cells tochemotherapeutic drug arsenic trioxide, by decreasing the cell viability, increasing the cellapoptosis rate, and enhancing intracellular accumulation of ROS. The results suggested thattargeting HO-1combined with chemotherapy drugs ATO supply a new way for the clinicaltreatment of osteosarcoma.
4The molecular mechanisms involved in which HO-1was highly induced by ATO
Objective: To investigate the molecular mechanisms of HO-1high expressioninduced by arsenic trioxide in human osteosarcoma cells. Methods: We used theinhibitor of mRNA polymeraseⅡ, Actinomycin-D (Act-D), and histone deacetylaseinhibitors to interfere with induction of HO-1by arsenic trioxide, in order to exclude interference of the stability of mRNA and the impact of histone acetylation. Weanalyzed HO-1expression by qRT-PCR and western blot. We extracted the protein oftranscription factor Nrf2with nucleoprotein extraction kit and used western blot andimmunocytochemistry to detect the expression of Nrf2in nucleus and cytoplasm.Results: Gene transcription inhibitors (Act-D) inhibited the induction of HO-1byarsenic trioxide significantly (P<0.01), suggesting that the increasing expression ofHO-1has nothing to do with stability of the mRNA; While TSA, sodium butyrate orother histone deacetylase inhibitors couldn’t change the HO-1expression apparently(P>0.05), suggesting the regulation in transcription has no obvious correlation withhistone acetylation. Along with the expression of HO-1increased, transcription factorNrf2targeting to antioxidant genes including HO-1expressed more in cell nucleus(P<0.01), and changed scarcely overall (P>0.05). Conclusions: Arsenic trioxideplayed a role in regulating the level of transcription on HO-1, and has nothing to dowith histone acetylation. The involved molecular mechanism was by increasing theexpression of transcription factor Nrf2in the nucleus and enhancing transcriptionlevel of target gene downstream exactly as HO-1.
方法：利用实时定量PCR及Western blot检测ATO对人骨肉瘤MG63及U2OS细胞HO-1诱导的表达；利用shRNA介导的RNA干扰技术阻断ATO对MG63及U2OS细胞中HO-1的诱导，研究其对细胞存活、凋亡、活性氧及对ATO敏感性等生物学行为的影响；应用免疫组织化学染色及Western blot等技术探讨ATO诱导HO-1表达的分子机制。
结果：首先，发现ATO特异性诱导了人骨肉瘤MG63及U2OS细胞HO-1的高度表达；然后，阻断HO-1的诱导后发现能够显著降低细胞对ATO的抗性，表现为明显降低细胞存活率，表现为细胞的凋亡明显增加，而与凋亡密切相关的细胞内ROS累积增多继而增加细胞对ATO的敏感性；另外，发现ATO上调HO-1的表达是通过增加转录因子Nrf2的入核，促进其在核中的转录活性进而调控下游靶基因HO-1的转录水平而发挥作用的。
结论：ATO特异性高幅度诱导了人骨肉瘤细胞HO-1的表达，阻断HO-1的诱导能够显著增加其对化疗药物ATO的敏感性。ATO诱导HO-1表达的分子机制是通过增加转录因子在细胞核中的转录活性，进而调控下游靶蛋白HO-1的表达来发挥作用的。HO-1在维持人骨肉瘤细胞对化疗药物ATO抗性中具有重要的作用，表现为通过清除肿瘤细胞内活性氧的累积继而抑制细胞的凋亡，从而促进细胞对ATO的耐药性。研究结果为研究骨肉瘤的生物学行为及分子机制提供了新的思路，为靶向HO-1的基因治疗配合药物化疗提供了理论依据。
1Highly induction of HO-1by ATO occurs specifically in human osteosarcomaMG63and U2OS cells
Arsenic trioxide (ATO) has been successfully used to treat leukemia and some solidmalignant tumors. But the effect to mesenchymal-derived human osteosarcoma cells andrelevant mechanism are unclear. From the toxic effects of arsenic trioxide on normalcells, oxidative damage plays a major role, so we first test changes of antioxidantgenes in human osteosarcoma MG63and U2OS cells under the induction of arsenictrioxide. Objective: To detect changes of antioxidant genes in human osteosarcomaMG63and U2OS cells which were treated with chemotherapy drugs arsenic trioxide.Methods: We used real-time PCR and Western blot methods to detect the mRNA andprotein expression of several kinds of antioxidant related genes after treatment witharsenic trioxide for24h. Results: HO-1mRNA was increased to more than80and120folds in human osteosarcoma MG63and U2OS cells respectively (P<0.01), whileother detected antioxidant genes changed little (P>0.05). HO-1protein was increasedto more than6and8folds in human osteosarcoma MG63and U2OS cellscorrespondingly (P<0.01). HO-1mRNA was increased to less than8folds and HO-1protein was increased to less than2folds in HUVECs after exposure to ATO.Conclusions: HO-1was highly induced in human osteosarcoma cells upon treatmentof ATO specifically.
2MG63and U2OS cells were transfected with shRNA-based vectors and stablesilenced cellclones were established
ATO could induce HO-1of human osteosarcoma cells highly expressspecifically. Since HO-1could remove reactive oxygen species (ROS) directly, andROS played an important role in apoptosis, we speculated that HO-1was contactedwith the resistance of osteosarcoma cells of arsenic trioxide. Objective: To clarify therole of gene HO-1in chemotherapy of osteosarcoma cells for arsenic trioxide, wedesigned and synthesized short hairpin based plasmid targeting gene of HO-1. Methods: We transfected the shRNA-mediated plasmid and scramble plasmid to MG63andU2OS cells by lipofectin transfection techniques. We got several single cell clonesthrough the resistance of G418and expression of red fluorescent protein. Results andconclusions: The stable silenced cell clones were established by shRNA-mediatedinterference.
3HO-1silencing enhanced ATO-mediated cell death in MG63and U2OSosteosarcoma cells
Objective: To investigate the role of HO-1in susceptibility of humanosteosarcoma cells to arsenic trioxide. To detect if there is any difference inHO-1-shRNA, scramble and parent cell groups, in order to study the pathogenesis ofosteosarcoma with multidrug-resistance and look for effective therapeutic measures.Methods: We analyzed the expression of gene HO-1in MG63and U2OS cells byreal-time PCR and Western blot after transfection. We used CellTiter-Glo assay todetect cell activity and IC50values of arsenic trioxide, and used AnnexinV-FITC/7-AAD and TUNEL assay to detect apoptotic cells, and determinedintracellular accumulation of reactive oxygen species with the ROS detection kit.Results: HO-1was silenced mainly in human osteosarcoma cells in spite of treatmentupon arsenic trioxide. Compared with parent and scramble groups, the apoptosis rateand intracellular accumulation of reactive oxygen species in HO-1silenced cellsincreased significantly in a dose-dependent and time-response effect (P<0.05). TheIC50values of HO-1-shRNA cells to arsenic trioxide were lower than parent andscramble cells (P<0.05). Conclusions: The resistance to arsenic trioxide of humanosteosarcoma MG63and U2OS cells was closely associated with the expression ofHO-1. Silencing HO-1increased the sensitivity of human osteosarcoma MG63cells tochemotherapeutic drug arsenic trioxide, by decreasing the cell viability, increasing the cellapoptosis rate, and enhancing intracellular accumulation of ROS. The results suggested thattargeting HO-1combined with chemotherapy drugs ATO supply a new way for the clinicaltreatment of osteosarcoma.
4The molecular mechanisms involved in which HO-1was highly induced by ATO
Objective: To investigate the molecular mechanisms of HO-1high expressioninduced by arsenic trioxide in human osteosarcoma cells. Methods: We used theinhibitor of mRNA polymeraseⅡ, Actinomycin-D (Act-D), and histone deacetylaseinhibitors to interfere with induction of HO-1by arsenic trioxide, in order to exclude interference of the stability of mRNA and the impact of histone acetylation. Weanalyzed HO-1expression by qRT-PCR and western blot. We extracted the protein oftranscription factor Nrf2with nucleoprotein extraction kit and used western blot andimmunocytochemistry to detect the expression of Nrf2in nucleus and cytoplasm.Results: Gene transcription inhibitors (Act-D) inhibited the induction of HO-1byarsenic trioxide significantly (P<0.01), suggesting that the increasing expression ofHO-1has nothing to do with stability of the mRNA; While TSA, sodium butyrate orother histone deacetylase inhibitors couldn’t change the HO-1expression apparently(P>0.05), suggesting the regulation in transcription has no obvious correlation withhistone acetylation. Along with the expression of HO-1increased, transcription factorNrf2targeting to antioxidant genes including HO-1expressed more in cell nucleus(P<0.01), and changed scarcely overall (P>0.05). Conclusions: Arsenic trioxideplayed a role in regulating the level of transcription on HO-1, and has nothing to dowith histone acetylation. The involved molecular mechanism was by increasing theexpression of transcription factor Nrf2in the nucleus and enhancing transcriptionlevel of target gene downstream exactly as HO-1.
引文
1. Picci, P., Osteosarcoma (osteogenic sarcoma). Orphanet J Rare Dis,2007.2: p.6.
2. Longhi, A., et al., Long-term follow-up of patients with doxorubicin-inducedcardiac toxicity after chemotherapy for osteosarcoma. Anticancer Drugs,2007.18(6): p.737-44.
3. Meyers, P.A., et al., Osteosarcoma: the addition of muramyl tripeptide tochemotherapy improves overall survival--a report from the Children'sOncology Group. J Clin Oncol,2008.26(4): p.633-8.
4. Sutow, W.W., et al., Study of adjuvant chemotherapy in osteogenic sarcoma. JClin Pharmacol,1975.15(7): p.530-3.
5. Tullo, A., A.M. D'Erchia, and E. Sbisa, Methods for screening tumors for p53status and therapeutic exploitation. Expert Rev Mol Diagn,2003.3(3): p.289-301.
6. Vogelstein, B., D. Lane, and A.J. Levine, Surfing the p53network. Nature,2000.408(6810): p.307-10.
7. Sharpless, N.E. and R.A. DePinho, Telomeres, stem cells, senescence, andcancer. J Clin Invest,2004.113(2): p.160-8.
8. Cong, Y.S., W.E. Wright, and J.W. Shay, Human telomerase and its regulation.Microbiol Mol Biol Rev,2002.66(3): p.407-25, table of contents.
9. Mergny, J.L., et al., Natural and pharmacological regulation of telomerase.Nucleic Acids Res,2002.30(4): p.839-65.
10. Shay, J.W. and S. Bacchetti, A survey of telomerase activity in human cancer.Eur J Cancer,1997.33(5): p.787-91.
11. Morin, G.B., The human telomere terminal transferase enzyme is aribonucleoprotein that synthesizes TTAGGG repeats. Cell,1989.59(3): p.521-9.
12.华海清,王锦鸿, and秦叔逵,砒霜古今应用探讨.中国中药杂志,2003.28(2): p.186-189.
13. Emadi, A. and S.D. Gore, Arsenic trioxide-An old drug rediscovered. BloodRev,2010.24(4-5): p.191-9.
14. Lo-Coco, F., et al., Retinoic acid and arsenic trioxide for acute promyelocyticleukemia. N Engl J Med,2013.369(2): p.111-21.
15. Mayor, S., Arsenic trioxide combination improves survival in APL. LancetOncol,2013.14(9): p. e346.
16. Mi, J.Q., et al., How to manage acute promyelocytic leukemia. Leukemia,2012.26(8): p.1743-51.
17. Chow, S.K., J.Y. Chan, and K.P. Fung, Inhibition of cell proliferation and theaction mechanisms of arsenic trioxide (As2O3) on human breast cancer cells. JCell Biochem,2004.93(1): p.173-87.
18. Mann, K.K., et al., Darinaparsin: a novel organic arsenical with promisinganticancer activity. Expert Opin Investig Drugs,2009.18(11): p.1727-34.
19. Kwong, Y.L. and D. Todd, Delicious poison: arsenic trioxide for the treatmentof leukemia. Blood,1997.89(9): p.3487-8.
20.左路, et al.,亚硒酸钠和三氧化二砷诱导人急性早幼粒细胞白血病细胞系NB4细胞凋亡机制的比较.中国实验血液学杂志,2002.10(3): p.195-200.
21.张鹏and胡龙虎,三氧化二砷治疗急性早幼粒细胞白血病的机制研究.白血病,1996.5(3): p.131-133.
22. Cai, X., et al., Arsenic trioxide-induced apoptosis and differentiation areassociated respectively with mitochondrial transmembrane potential collapseand retinoic acid signaling pathways in acute promyelocytic leukemia.Leukemia,2000.14(2): p.262-70.
23.蔡洪培,邓志华, and李石, As2O3诱导人胃癌细胞凋亡的研究.第二军医大学学报,1999.20(9): p.636-639.
24.顾琴龙and沈佰华,氧化砷诱发胃癌细胞株凋亡的初步研究.中华消化杂志,1998.18(2): p.69-71.
25. Testa, U., et al., The PML/RARalpha fusion protein inhibits tumor necrosisfactor-alpha-induced apoptosis in U937cells and acute promyelocyticleukemia blasts. J Clin Invest,1998.101(10): p.2278-89.
26.刘铁夫, et al., CD44基因编码蛋白表达与三氧化二砷抗肿瘤作用关系的研究.哈尔滨医科大学学报,2001.35(2): p.111-112.
27.石熠慧, et al., AS_2O_3对消化道肿瘤细胞凋亡作用的研究.上海第二医科大学学报,1999.3: p.014.
28.董继华, et al.,三氧化二砷对人肺癌细胞株增殖和凋亡的影响.中国肺癌杂志,2000.3(6): p.435-437.
29.师晶玉, et al.,三氧化二砷对人肺腺癌Anip973细胞内[Ca2+] i的影响.哈尔滨医科大学学报,2004.38(2): p.146-148.
30. Smith, A.H., et al., Chronic respiratory symptoms in children following inutero and early life exposure to arsenic in drinking water in Bangladesh. Int JEpidemiol,2013.42(4): p.1077-86.
31.陈黎明,三氧化二砷体外诱导口腔鳞癌细胞凋亡的研究.第三军医大学学报,2003.25(6): p.546-548.
32. Nakaoka, T., et al., Combined arsenic trioxide-cisplatin treatment enhancesapoptosis in oral squamous cell carcinoma cells. Cell Oncol (Dordr),2014.
33. Sides, M.D., et al., Co-treatment with arsenic trioxide and ganciclovir reducestumor volume in a murine xenograft model of nasopharyngeal carcinoma.Virol J,2013.10: p.152.
34.杜彩文, et al.,三氧化二砷诱导人鼻咽低分化鳞癌裸鼠移植瘤细胞分化的研究.癌症,2003.22(1): p.21-25.
35.李德锐, et al.,三氧化二砷对人鼻咽癌小鼠移植瘤生长抑制和诱导分化的初步研究.汕头大学医学院学报,2003.16(1): p.1-3.
36. Kodigepalli, K.M., et al., SnoN/SkiL expression is modulated via arsenictrioxide-induced activation of the PI3K/AKT pathway in ovarian cancer cells.FEBS Lett,2013.587(1): p.5-16.
37. Smith, D.M., et al., Arsenic trioxide induces a beclin-1-independentautophagic pathway via modulation of SnoN/SkiL expression in ovariancarcinoma cells. Cell Death Differ,2010.17(12): p.1867-81.
38.黄守国, et al.,三氧化二砷对人卵巢癌耐药细胞株细胞增殖和转移能力的影响.癌症,2002.21(8): p.863-867.
39.黄守国, et al.,三氧化二砷诱导人卵巢癌细胞凋亡机制的研究.肿瘤防治杂志,2002.9(2): p.154-156.
40. Wen, X., et al., Arsenic trioxide induces cervical cancer apoptosis, butspecifically targets human papillomavirus-infected cell populations.Anticancer Drugs,2012.23(3): p.280-7.
41.邓友平, et al.,三氧化二砷诱导人宫颈癌HeLa细胞凋亡及Bcl-2保护作用的机制研究.中国科学C辑,1999.29(4): p.426-426.
42.刘明远,侯霞, and马洪星,三氧化二砷诱导Hela细胞凋亡的机制研究.黑龙江医药科学,2002.25(5): p.50-51.
43.吕秀宁and郑杰, As2O3诱导宫颈癌HeLa细胞凋亡与细胞内端粒酶活性关系的研究.东南大学学报:医学版,2003.22(4): p.227-229.
44. Liu, W., et al., Arsenic trioxide-induced growth arrest of breast cancer MCF-7cells involving FOXO3a and IkappaB kinase beta expression and localization.Cancer Biother Radiopharm,2012.27(8): p.504-12.
45. Sun, R.C., P.G. Board, and A.C. Blackburn, Targeting metabolism with arsenictrioxide and dichloroacetate in breast cancer cells. Mol Cancer,2011.10: p.142.
46. Nakagawa, Y., et al., Arsenic trioxide-induced apoptosis through oxidativestress in cells of colon cancer cell lines. Life Sci,2002.70(19): p.2253-69.
47.陈鑫and吴诚义,三氧化二砷对人乳腺癌裸鼠移植瘤的作用.中华实验外科杂志,2003.20(8): p.722-723.
48.陆地, et al.,三氧化二砷诱导人类恶性淋巴瘤细胞凋亡及机制探讨.第一军医大学学报,2003.23(10): p.997-1101.
49.童强松, et al.,三氧化二砷抑制人膀胱癌细胞BIU-87体外生长的实验研究.临床泌尿外科杂志,2000.15(2): p.72-74.
50. Akao, Y., H. Yamada, and Y. Nakagawa, Arsenic-induced apoptosis inmalignant cells in vitro. Leuk Lymphoma,2000.37(1-2): p.53-63.
51. Seol, J.G., et al., Effect of arsenic trioxide on cell cycle arrest in head and neckcancer cell line PCI-1. Biochem Biophys Res Commun,1999.265(2): p.400-4.
52. Ahn, R.W., et al., A novel nanoparticulate formulation of arsenic trioxide withenhanced therapeutic efficacy in a murine model of breast cancer. Clin CancerRes,2010.16(14): p.3607-17.
53.刘建伟, et al.,三氧化二砷和尿多酸肽抗肝癌作用的协同效应.中华普通外科杂志,2003.18(2): p.114-116.
54.刘建伟, et al.,三氧化二砷和细胞分化剂诱导肝癌细胞凋亡的阈值.中华实验外科杂志,2003.20(2): p.116-117.
55. Andoh, Y., et al., Low-and high-level expressions of heme oxygenase-1incultured cells under uninduced conditions. Biochem Biophys Res Commun,2004.320(3): p.722-9.
56. Maines, M.D. and P.E. Gibbs,30some years of heme oxygenase: from a"molecular wrecking ball" to a "mesmerizing" trigger of cellular events.Biochem Biophys Res Commun,2005.338(1): p.568-77.
57. Hill, M., et al., Heme oxygenase-1inhibits rat and human breast cancer cellproliferation: mutual cross inhibition with indoleamine2,3-dioxygenase.FASEB J,2005.19(14): p.1957-68.
58. Poss, K.D. and S. Tonegawa, Heme oxygenase1is required for mammalianiron reutilization. Proc Natl Acad Sci U S A,1997.94(20): p.10919-24.
59. Inguaggiato, P., et al., Cellular overexpression of heme oxygenase-1up-regulates p21and confers resistance to apoptosis. Kidney Int,2001.60(6):p.2181-91.
60. Coito, A.J., et al., Heme oxygenase-1gene transfer inhibits inducible nitricoxide synthase expression and protects genetically fat Zucker rat livers fromischemia-reperfusion injury. Transplantation,2002.74(1): p.96-102.
61. Genter, M.B., et al., Genomic analysis of alachlor-induced oncogenesis in ratolfactory mucosa. Physiol Genomics,2002.12(1): p.35-45.
62. Caballero, F., et al., Immunohistochemical analysis of heme oxygenase-1inpreneoplastic and neoplastic lesions during chemical hepatocarcinogenesis. IntJ Exp Pathol,2004.85(4): p.213-22.
63. Kukoba, T.V. and O.O. Moibenko,[Heme oxygenase and carbon monoxide:the protection or the injury of cells?]. Fiziol Zh,2002.48(5): p.79-92.
64. Maines, M.D. and P.A. Abrahamsson, Expression of heme oxygenase-1(HSP32) in human prostate: normal, hyperplastic, and tumor tissuedistribution. Urology,1996.47(5): p.727-33.
65. Tsuji, M.H., et al., Heme oxygenase-1expression in oral squamous cellcarcinoma as involved in lymph node metastasis. Cancer Lett,1999.138(1-2):p.53-9.
66. Motohashi, H. and M. Yamamoto, Nrf2-Keap1defines a physiologicallyimportant stress response mechanism. Trends Mol Med,2004.10(11): p.549-57.
67. Kobayashi, A., T. Ohta, and M. Yamamoto, Unique function of theNrf2-Keap1pathway in the inducible expression of antioxidant anddetoxifying enzymes. Methods Enzymol,2004.378: p.273-86.
68. Cullinan, S.B., et al., Nrf2is a direct PERK substrate and effector ofPERK-dependent cell survival. Mol Cell Biol,2003.23(20): p.7198-209.
69. Kang, K.W., et al., Phosphatidylinositol3-kinase regulates nucleartranslocation of NF-E2-related factor2through actin rearrangement inresponse to oxidative stress. Mol Pharmacol,2002.62(5): p.1001-10.
70. Keum, Y.S., et al., Mechanism of action of sulforaphane: inhibition of p38mitogen-activated protein kinase isoforms contributing to the induction ofantioxidant response element-mediated heme oxygenase-1in human hepatomaHepG2cells. Cancer Res,2006.66(17): p.8804-13.
71. Gupta, G.R., et al., Risk of local recurrence after deltoid-sparing resection forosteosarcoma of the proximal humerus. Cancer,2009.115(16): p.3767-73.
72. Messerschmitt, P.J., et al., Osteosarcoma. J Am Acad Orthop Surg,2009.17(8):p.515-27.
73. Grimer, R.J., Surgical options for children with osteosarcoma. Lancet Oncol,2005.6(2): p.85-92.
74. Scully, S.P., et al., Pathologic fracture in osteosarcoma: prognostic importanceand treatment implications. J Bone Joint Surg Am,2002.84-A(1): p.49-57.
75. Sampo, M., et al., Incidence, epidemiology and treatment results ofosteosarcoma in Finland-a nationwide population-based study. Acta Oncol,2011.50(8): p.1206-14.
76. Hameed, M. and H. Dorfman, Primary malignant bone tumors--recentdevelopments. Semin Diagn Pathol,2011.28(1): p.86-101.
77. Ferrari, S. and E. Palmerini, Adjuvant and neoadjuvant combinationchemotherapy for osteogenic sarcoma. Curr Opin Oncol,2007.19(4): p.341-6.
78. Marina, N., et al., Biology and therapeutic advances for pediatricosteosarcoma. Oncologist,2004.9(4): p.422-41.
79. Bacci, G., et al., Neoadjuvant chemotherapy for osteosarcoma of the extremity:intensification of preoperative treatment does not increase the rate of goodhistologic response to the primary tumor or improve the final outcome. JPediatr Hematol Oncol,2003.25(11): p.845-53.
80. Meyers, P.A., et al., Osteosarcoma: a randomized, prospective trial of theaddition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, andhigh-dose methotrexate. J Clin Oncol,2005.23(9): p.2004-11.
81. Shen, Z.Y., et al., Morphological and functional changes of mitochondria inapoptotic esophageal carcinoma cells induced by arsenic trioxide. World JGastroenterol,2002.8(1): p.31-5.
82. Lu, T.H., et al., Arsenic induces reactive oxygen species-caused neuronal cellapoptosis through JNK/ERK-mediated mitochondria-dependent and GRP78/CHOP-regulated pathways. Toxicol Lett,2014.224(1): p.130-40.
83. Lu, T.H., et al., Arsenic induces pancreatic beta-cell apoptosis via theoxidative stress-regulated mitochondria-dependent and endoplasmic reticulumstress-triggered signaling pathways. Toxicol Lett,2011.201(1): p.15-26.
84. Zhu, X.H., et al., Apoptosis and growth inhibition in malignant lymphocytesafter treatment with arsenic trioxide at clinically achievable concentrations. JNatl Cancer Inst,1999.91(9): p.772-8.
85. Tanaka, Y., et al., BIMEL is a key effector molecule in oxidativestress-mediated apoptosis in acute myeloid leukemia cells when combinedwith arsenic trioxide and buthionine sulfoximine. BMC Cancer,2014.14(1): p.27.
86. Alarifi, S., et al., Arsenic trioxide-mediated oxidative stress and genotoxicityin human hepatocellular carcinoma cells. Onco Targets Ther,2013.6: p.75-84.
87. Qin, X., C. Qiu, and L. Zhao, Maslinic acid protects vascular smooth musclecells from oxidative stress through Akt/Nrf2/HO-1pathway. Mol CellBiochem,2014.
88. Zhang, H., et al., Salvianolic acid A protects RPE cells against oxidative stressthrough activation of Nrf2/HO-1signaling. Free Radic Biol Med,2014.69: p.219-28.
89. Bramwell, V.H., The role of chemotherapy in osteogenic sarcoma. Crit RevOncol Hematol,1995.20(1-2): p.61-85.
90. Hu, X.M., et al., Arsenic disulfide induced apoptosis and concurrentlypromoted erythroid differentiation in cytokine-dependent myelodysplasticsyndrome-progressed leukemia cell line F-36p with complex karyotypeincluding monosomy7. Chin J Integr Med,2014.
91. Hu, X.M., et al., Arsenic disulfide-triggered apoptosis and erythroiddifferentiation in myelodysplastic syndrome and acute myeloid leukemia celllines. Hematology,2013.
92. Zhuang, C., et al., Updated Research and Applications of Small MoleculeInhibitors of Keap1-Nrf2Protein-Protein Interaction: a Review. Curr MedChem,2014.
93. Wang, X.J., et al., Oxaliplatin activates the Keap1/Nrf2antioxidant systemconferring protection against the cytotoxicity of anticancer drugs. Free RadicBiol Med,2014.70C: p.68-77.
94. Cordova, E.J., et al., The NRF2-KEAP1Pathway Is an Early Responsive GeneNetwork in Arsenic Exposed Lymphoblastoid Cells. PLoS One,2014.9(2): p.e88069.
95. Park, J.Y., Y.W. Kim, and Y.K. Park, Nrf2expression is associated with pooroutcome in osteosarcoma. Pathology,2012.44(7): p.617-21.
96. Kansanen, E., et al., The Keap1-Nrf2pathway: Mechanisms of activation anddysregulation in cancer. Redox Biol,2013.1(1): p.45-49.
97. Engel, R.H. and A.M. Evens, Oxidative stress and apoptosis: a new treatmentparadigm in cancer. Front Biosci,2006.11: p.300-12.
98. Liu, S.X., et al., Induction of oxyradicals by arsenic: implication formechanism of genotoxicity. Proc Natl Acad Sci U S A,2001.98(4): p.1643-8.
99. Wang, L.W., et al., Association of oxidative stress with realgar-induceddifferentiation in human leukemia HL-60cells. Chemotherapy,2009.55(6): p.460-7.
100. Ueda, Y., et al., Analysis of mutant P53protein in osteosarcomas and othermalignant and benign lesions of bone. J Cancer Res Clin Oncol,1993.119(3):p.172-8.
101. Overholtzer, M., et al., The presence of p53mutations in humanosteosarcomas correlates with high levels of genomic instability. Proc NatlAcad Sci U S A,2003.100(20): p.11547-52.
102. Goto, A., et al., Association of loss of heterozygosity at the p53locus withchemoresistance in osteosarcomas. Jpn J Cancer Res,1998.89(5): p.539-47.
103. Gimenez-Bonafe, P., A. Tortosa, and R. Perez-Tomas, Overcoming drugresistance by enhancing apoptosis of tumor cells. Curr Cancer Drug Targets,2009.9(3): p.320-40.
104. Raikhlin, N.T., E.A. Smirnov, and A.G. Perevoshchikov,[Apoptosis and itsrole in the mechanisms of growth regulation of tumor cells with multiple drugresistance]. Arkh Patol,1996.58(2): p.3-8.
105. Yedjou, C.G., P. Moore, and P.B. Tchounwou, Dose-and time-dependentresponse of human leukemia (HL-60) cells to arsenic trioxide treatment. Int JEnviron Res Public Health,2006.3(2): p.136-40.
106. Yong, Y., et al., Dichamanetin inhibits cancer cell growth by affectingROS-related signaling components through mitochondrial-mediated apoptosis.Anticancer Res,2013.33(12): p.5349-55.
107. Chen, S., et al., N-acetyl-L-cysteine protects against cadmium-inducedneuronal apoptosis by inhibiting ROS-dependent activation of Akt/mTORpathway in mouse brain. Neuropathol Appl Neurobiol,2013.
108. An, J.J., et al., The ROS/JNK/ATF2pathway mediates selenite-inducedleukemia NB4cell cycle arrest and apoptosis in vitro and in vivo. Cell DeathDis,2013.4: p. e973.
109. Sanchez, Y., et al., Modulation of arsenic trioxide-induced apoptosis bygenistein and functionally related agents in U937human leukaemia cells.Regulation by ROS and mitogen-activated protein kinases. Chem Biol Interact,2009.182(1): p.37-44.
110. Wang, Y., et al., Arsenic induces mitochondria-dependent apoptosis by reactiveoxygen species generation rather than glutathione depletion in Chang humanhepatocytes. Arch Toxicol,2009.83(10): p.899-908.
111. Das, J., et al., Taurine protects rat testes against NaAsO2-induced oxidativestress and apoptosis via mitochondrial dependent and independent pathways.Toxicol Lett,2009.187(3): p.201-10.
2. Longhi, A., et al., Long-term follow-up of patients with doxorubicin-inducedcardiac toxicity after chemotherapy for osteosarcoma. Anticancer Drugs,2007.18(6): p.737-44.
3. Meyers, P.A., et al., Osteosarcoma: the addition of muramyl tripeptide tochemotherapy improves overall survival--a report from the Children'sOncology Group. J Clin Oncol,2008.26(4): p.633-8.
4. Sutow, W.W., et al., Study of adjuvant chemotherapy in osteogenic sarcoma. JClin Pharmacol,1975.15(7): p.530-3.
5. Tullo, A., A.M. D'Erchia, and E. Sbisa, Methods for screening tumors for p53status and therapeutic exploitation. Expert Rev Mol Diagn,2003.3(3): p.289-301.
6. Vogelstein, B., D. Lane, and A.J. Levine, Surfing the p53network. Nature,2000.408(6810): p.307-10.
7. Sharpless, N.E. and R.A. DePinho, Telomeres, stem cells, senescence, andcancer. J Clin Invest,2004.113(2): p.160-8.
8. Cong, Y.S., W.E. Wright, and J.W. Shay, Human telomerase and its regulation.Microbiol Mol Biol Rev,2002.66(3): p.407-25, table of contents.
9. Mergny, J.L., et al., Natural and pharmacological regulation of telomerase.Nucleic Acids Res,2002.30(4): p.839-65.
10. Shay, J.W. and S. Bacchetti, A survey of telomerase activity in human cancer.Eur J Cancer,1997.33(5): p.787-91.
11. Morin, G.B., The human telomere terminal transferase enzyme is aribonucleoprotein that synthesizes TTAGGG repeats. Cell,1989.59(3): p.521-9.
12.华海清,王锦鸿, and秦叔逵,砒霜古今应用探讨.中国中药杂志,2003.28(2): p.186-189.
13. Emadi, A. and S.D. Gore, Arsenic trioxide-An old drug rediscovered. BloodRev,2010.24(4-5): p.191-9.
14. Lo-Coco, F., et al., Retinoic acid and arsenic trioxide for acute promyelocyticleukemia. N Engl J Med,2013.369(2): p.111-21.
15. Mayor, S., Arsenic trioxide combination improves survival in APL. LancetOncol,2013.14(9): p. e346.
16. Mi, J.Q., et al., How to manage acute promyelocytic leukemia. Leukemia,2012.26(8): p.1743-51.
17. Chow, S.K., J.Y. Chan, and K.P. Fung, Inhibition of cell proliferation and theaction mechanisms of arsenic trioxide (As2O3) on human breast cancer cells. JCell Biochem,2004.93(1): p.173-87.
18. Mann, K.K., et al., Darinaparsin: a novel organic arsenical with promisinganticancer activity. Expert Opin Investig Drugs,2009.18(11): p.1727-34.
19. Kwong, Y.L. and D. Todd, Delicious poison: arsenic trioxide for the treatmentof leukemia. Blood,1997.89(9): p.3487-8.
20.左路, et al.,亚硒酸钠和三氧化二砷诱导人急性早幼粒细胞白血病细胞系NB4细胞凋亡机制的比较.中国实验血液学杂志,2002.10(3): p.195-200.
21.张鹏and胡龙虎,三氧化二砷治疗急性早幼粒细胞白血病的机制研究.白血病,1996.5(3): p.131-133.
22. Cai, X., et al., Arsenic trioxide-induced apoptosis and differentiation areassociated respectively with mitochondrial transmembrane potential collapseand retinoic acid signaling pathways in acute promyelocytic leukemia.Leukemia,2000.14(2): p.262-70.
23.蔡洪培,邓志华, and李石, As2O3诱导人胃癌细胞凋亡的研究.第二军医大学学报,1999.20(9): p.636-639.
24.顾琴龙and沈佰华,氧化砷诱发胃癌细胞株凋亡的初步研究.中华消化杂志,1998.18(2): p.69-71.
25. Testa, U., et al., The PML/RARalpha fusion protein inhibits tumor necrosisfactor-alpha-induced apoptosis in U937cells and acute promyelocyticleukemia blasts. J Clin Invest,1998.101(10): p.2278-89.
26.刘铁夫, et al., CD44基因编码蛋白表达与三氧化二砷抗肿瘤作用关系的研究.哈尔滨医科大学学报,2001.35(2): p.111-112.
27.石熠慧, et al., AS_2O_3对消化道肿瘤细胞凋亡作用的研究.上海第二医科大学学报,1999.3: p.014.
28.董继华, et al.,三氧化二砷对人肺癌细胞株增殖和凋亡的影响.中国肺癌杂志,2000.3(6): p.435-437.
29.师晶玉, et al.,三氧化二砷对人肺腺癌Anip973细胞内[Ca2+] i的影响.哈尔滨医科大学学报,2004.38(2): p.146-148.
30. Smith, A.H., et al., Chronic respiratory symptoms in children following inutero and early life exposure to arsenic in drinking water in Bangladesh. Int JEpidemiol,2013.42(4): p.1077-86.
31.陈黎明,三氧化二砷体外诱导口腔鳞癌细胞凋亡的研究.第三军医大学学报,2003.25(6): p.546-548.
32. Nakaoka, T., et al., Combined arsenic trioxide-cisplatin treatment enhancesapoptosis in oral squamous cell carcinoma cells. Cell Oncol (Dordr),2014.
33. Sides, M.D., et al., Co-treatment with arsenic trioxide and ganciclovir reducestumor volume in a murine xenograft model of nasopharyngeal carcinoma.Virol J,2013.10: p.152.
34.杜彩文, et al.,三氧化二砷诱导人鼻咽低分化鳞癌裸鼠移植瘤细胞分化的研究.癌症,2003.22(1): p.21-25.
35.李德锐, et al.,三氧化二砷对人鼻咽癌小鼠移植瘤生长抑制和诱导分化的初步研究.汕头大学医学院学报,2003.16(1): p.1-3.
36. Kodigepalli, K.M., et al., SnoN/SkiL expression is modulated via arsenictrioxide-induced activation of the PI3K/AKT pathway in ovarian cancer cells.FEBS Lett,2013.587(1): p.5-16.
37. Smith, D.M., et al., Arsenic trioxide induces a beclin-1-independentautophagic pathway via modulation of SnoN/SkiL expression in ovariancarcinoma cells. Cell Death Differ,2010.17(12): p.1867-81.
38.黄守国, et al.,三氧化二砷对人卵巢癌耐药细胞株细胞增殖和转移能力的影响.癌症,2002.21(8): p.863-867.
39.黄守国, et al.,三氧化二砷诱导人卵巢癌细胞凋亡机制的研究.肿瘤防治杂志,2002.9(2): p.154-156.
40. Wen, X., et al., Arsenic trioxide induces cervical cancer apoptosis, butspecifically targets human papillomavirus-infected cell populations.Anticancer Drugs,2012.23(3): p.280-7.
41.邓友平, et al.,三氧化二砷诱导人宫颈癌HeLa细胞凋亡及Bcl-2保护作用的机制研究.中国科学C辑,1999.29(4): p.426-426.
42.刘明远,侯霞, and马洪星,三氧化二砷诱导Hela细胞凋亡的机制研究.黑龙江医药科学,2002.25(5): p.50-51.
43.吕秀宁and郑杰, As2O3诱导宫颈癌HeLa细胞凋亡与细胞内端粒酶活性关系的研究.东南大学学报:医学版,2003.22(4): p.227-229.
44. Liu, W., et al., Arsenic trioxide-induced growth arrest of breast cancer MCF-7cells involving FOXO3a and IkappaB kinase beta expression and localization.Cancer Biother Radiopharm,2012.27(8): p.504-12.
45. Sun, R.C., P.G. Board, and A.C. Blackburn, Targeting metabolism with arsenictrioxide and dichloroacetate in breast cancer cells. Mol Cancer,2011.10: p.142.
46. Nakagawa, Y., et al., Arsenic trioxide-induced apoptosis through oxidativestress in cells of colon cancer cell lines. Life Sci,2002.70(19): p.2253-69.
47.陈鑫and吴诚义,三氧化二砷对人乳腺癌裸鼠移植瘤的作用.中华实验外科杂志,2003.20(8): p.722-723.
48.陆地, et al.,三氧化二砷诱导人类恶性淋巴瘤细胞凋亡及机制探讨.第一军医大学学报,2003.23(10): p.997-1101.
49.童强松, et al.,三氧化二砷抑制人膀胱癌细胞BIU-87体外生长的实验研究.临床泌尿外科杂志,2000.15(2): p.72-74.
50. Akao, Y., H. Yamada, and Y. Nakagawa, Arsenic-induced apoptosis inmalignant cells in vitro. Leuk Lymphoma,2000.37(1-2): p.53-63.
51. Seol, J.G., et al., Effect of arsenic trioxide on cell cycle arrest in head and neckcancer cell line PCI-1. Biochem Biophys Res Commun,1999.265(2): p.400-4.
52. Ahn, R.W., et al., A novel nanoparticulate formulation of arsenic trioxide withenhanced therapeutic efficacy in a murine model of breast cancer. Clin CancerRes,2010.16(14): p.3607-17.
53.刘建伟, et al.,三氧化二砷和尿多酸肽抗肝癌作用的协同效应.中华普通外科杂志,2003.18(2): p.114-116.
54.刘建伟, et al.,三氧化二砷和细胞分化剂诱导肝癌细胞凋亡的阈值.中华实验外科杂志,2003.20(2): p.116-117.
55. Andoh, Y., et al., Low-and high-level expressions of heme oxygenase-1incultured cells under uninduced conditions. Biochem Biophys Res Commun,2004.320(3): p.722-9.
56. Maines, M.D. and P.E. Gibbs,30some years of heme oxygenase: from a"molecular wrecking ball" to a "mesmerizing" trigger of cellular events.Biochem Biophys Res Commun,2005.338(1): p.568-77.
57. Hill, M., et al., Heme oxygenase-1inhibits rat and human breast cancer cellproliferation: mutual cross inhibition with indoleamine2,3-dioxygenase.FASEB J,2005.19(14): p.1957-68.
58. Poss, K.D. and S. Tonegawa, Heme oxygenase1is required for mammalianiron reutilization. Proc Natl Acad Sci U S A,1997.94(20): p.10919-24.
59. Inguaggiato, P., et al., Cellular overexpression of heme oxygenase-1up-regulates p21and confers resistance to apoptosis. Kidney Int,2001.60(6):p.2181-91.
60. Coito, A.J., et al., Heme oxygenase-1gene transfer inhibits inducible nitricoxide synthase expression and protects genetically fat Zucker rat livers fromischemia-reperfusion injury. Transplantation,2002.74(1): p.96-102.
61. Genter, M.B., et al., Genomic analysis of alachlor-induced oncogenesis in ratolfactory mucosa. Physiol Genomics,2002.12(1): p.35-45.
62. Caballero, F., et al., Immunohistochemical analysis of heme oxygenase-1inpreneoplastic and neoplastic lesions during chemical hepatocarcinogenesis. IntJ Exp Pathol,2004.85(4): p.213-22.
63. Kukoba, T.V. and O.O. Moibenko,[Heme oxygenase and carbon monoxide:the protection or the injury of cells?]. Fiziol Zh,2002.48(5): p.79-92.
64. Maines, M.D. and P.A. Abrahamsson, Expression of heme oxygenase-1(HSP32) in human prostate: normal, hyperplastic, and tumor tissuedistribution. Urology,1996.47(5): p.727-33.
65. Tsuji, M.H., et al., Heme oxygenase-1expression in oral squamous cellcarcinoma as involved in lymph node metastasis. Cancer Lett,1999.138(1-2):p.53-9.
66. Motohashi, H. and M. Yamamoto, Nrf2-Keap1defines a physiologicallyimportant stress response mechanism. Trends Mol Med,2004.10(11): p.549-57.
67. Kobayashi, A., T. Ohta, and M. Yamamoto, Unique function of theNrf2-Keap1pathway in the inducible expression of antioxidant anddetoxifying enzymes. Methods Enzymol,2004.378: p.273-86.
68. Cullinan, S.B., et al., Nrf2is a direct PERK substrate and effector ofPERK-dependent cell survival. Mol Cell Biol,2003.23(20): p.7198-209.
69. Kang, K.W., et al., Phosphatidylinositol3-kinase regulates nucleartranslocation of NF-E2-related factor2through actin rearrangement inresponse to oxidative stress. Mol Pharmacol,2002.62(5): p.1001-10.
70. Keum, Y.S., et al., Mechanism of action of sulforaphane: inhibition of p38mitogen-activated protein kinase isoforms contributing to the induction ofantioxidant response element-mediated heme oxygenase-1in human hepatomaHepG2cells. Cancer Res,2006.66(17): p.8804-13.
71. Gupta, G.R., et al., Risk of local recurrence after deltoid-sparing resection forosteosarcoma of the proximal humerus. Cancer,2009.115(16): p.3767-73.
72. Messerschmitt, P.J., et al., Osteosarcoma. J Am Acad Orthop Surg,2009.17(8):p.515-27.
73. Grimer, R.J., Surgical options for children with osteosarcoma. Lancet Oncol,2005.6(2): p.85-92.
74. Scully, S.P., et al., Pathologic fracture in osteosarcoma: prognostic importanceand treatment implications. J Bone Joint Surg Am,2002.84-A(1): p.49-57.
75. Sampo, M., et al., Incidence, epidemiology and treatment results ofosteosarcoma in Finland-a nationwide population-based study. Acta Oncol,2011.50(8): p.1206-14.
76. Hameed, M. and H. Dorfman, Primary malignant bone tumors--recentdevelopments. Semin Diagn Pathol,2011.28(1): p.86-101.
77. Ferrari, S. and E. Palmerini, Adjuvant and neoadjuvant combinationchemotherapy for osteogenic sarcoma. Curr Opin Oncol,2007.19(4): p.341-6.
78. Marina, N., et al., Biology and therapeutic advances for pediatricosteosarcoma. Oncologist,2004.9(4): p.422-41.
79. Bacci, G., et al., Neoadjuvant chemotherapy for osteosarcoma of the extremity:intensification of preoperative treatment does not increase the rate of goodhistologic response to the primary tumor or improve the final outcome. JPediatr Hematol Oncol,2003.25(11): p.845-53.
80. Meyers, P.A., et al., Osteosarcoma: a randomized, prospective trial of theaddition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, andhigh-dose methotrexate. J Clin Oncol,2005.23(9): p.2004-11.
81. Shen, Z.Y., et al., Morphological and functional changes of mitochondria inapoptotic esophageal carcinoma cells induced by arsenic trioxide. World JGastroenterol,2002.8(1): p.31-5.
82. Lu, T.H., et al., Arsenic induces reactive oxygen species-caused neuronal cellapoptosis through JNK/ERK-mediated mitochondria-dependent and GRP78/CHOP-regulated pathways. Toxicol Lett,2014.224(1): p.130-40.
83. Lu, T.H., et al., Arsenic induces pancreatic beta-cell apoptosis via theoxidative stress-regulated mitochondria-dependent and endoplasmic reticulumstress-triggered signaling pathways. Toxicol Lett,2011.201(1): p.15-26.
84. Zhu, X.H., et al., Apoptosis and growth inhibition in malignant lymphocytesafter treatment with arsenic trioxide at clinically achievable concentrations. JNatl Cancer Inst,1999.91(9): p.772-8.
85. Tanaka, Y., et al., BIMEL is a key effector molecule in oxidativestress-mediated apoptosis in acute myeloid leukemia cells when combinedwith arsenic trioxide and buthionine sulfoximine. BMC Cancer,2014.14(1): p.27.
86. Alarifi, S., et al., Arsenic trioxide-mediated oxidative stress and genotoxicityin human hepatocellular carcinoma cells. Onco Targets Ther,2013.6: p.75-84.
87. Qin, X., C. Qiu, and L. Zhao, Maslinic acid protects vascular smooth musclecells from oxidative stress through Akt/Nrf2/HO-1pathway. Mol CellBiochem,2014.
88. Zhang, H., et al., Salvianolic acid A protects RPE cells against oxidative stressthrough activation of Nrf2/HO-1signaling. Free Radic Biol Med,2014.69: p.219-28.
89. Bramwell, V.H., The role of chemotherapy in osteogenic sarcoma. Crit RevOncol Hematol,1995.20(1-2): p.61-85.
90. Hu, X.M., et al., Arsenic disulfide induced apoptosis and concurrentlypromoted erythroid differentiation in cytokine-dependent myelodysplasticsyndrome-progressed leukemia cell line F-36p with complex karyotypeincluding monosomy7. Chin J Integr Med,2014.
91. Hu, X.M., et al., Arsenic disulfide-triggered apoptosis and erythroiddifferentiation in myelodysplastic syndrome and acute myeloid leukemia celllines. Hematology,2013.
92. Zhuang, C., et al., Updated Research and Applications of Small MoleculeInhibitors of Keap1-Nrf2Protein-Protein Interaction: a Review. Curr MedChem,2014.
93. Wang, X.J., et al., Oxaliplatin activates the Keap1/Nrf2antioxidant systemconferring protection against the cytotoxicity of anticancer drugs. Free RadicBiol Med,2014.70C: p.68-77.
94. Cordova, E.J., et al., The NRF2-KEAP1Pathway Is an Early Responsive GeneNetwork in Arsenic Exposed Lymphoblastoid Cells. PLoS One,2014.9(2): p.e88069.
95. Park, J.Y., Y.W. Kim, and Y.K. Park, Nrf2expression is associated with pooroutcome in osteosarcoma. Pathology,2012.44(7): p.617-21.
96. Kansanen, E., et al., The Keap1-Nrf2pathway: Mechanisms of activation anddysregulation in cancer. Redox Biol,2013.1(1): p.45-49.
97. Engel, R.H. and A.M. Evens, Oxidative stress and apoptosis: a new treatmentparadigm in cancer. Front Biosci,2006.11: p.300-12.
98. Liu, S.X., et al., Induction of oxyradicals by arsenic: implication formechanism of genotoxicity. Proc Natl Acad Sci U S A,2001.98(4): p.1643-8.
99. Wang, L.W., et al., Association of oxidative stress with realgar-induceddifferentiation in human leukemia HL-60cells. Chemotherapy,2009.55(6): p.460-7.
100. Ueda, Y., et al., Analysis of mutant P53protein in osteosarcomas and othermalignant and benign lesions of bone. J Cancer Res Clin Oncol,1993.119(3):p.172-8.
101. Overholtzer, M., et al., The presence of p53mutations in humanosteosarcomas correlates with high levels of genomic instability. Proc NatlAcad Sci U S A,2003.100(20): p.11547-52.
102. Goto, A., et al., Association of loss of heterozygosity at the p53locus withchemoresistance in osteosarcomas. Jpn J Cancer Res,1998.89(5): p.539-47.
103. Gimenez-Bonafe, P., A. Tortosa, and R. Perez-Tomas, Overcoming drugresistance by enhancing apoptosis of tumor cells. Curr Cancer Drug Targets,2009.9(3): p.320-40.
104. Raikhlin, N.T., E.A. Smirnov, and A.G. Perevoshchikov,[Apoptosis and itsrole in the mechanisms of growth regulation of tumor cells with multiple drugresistance]. Arkh Patol,1996.58(2): p.3-8.
105. Yedjou, C.G., P. Moore, and P.B. Tchounwou, Dose-and time-dependentresponse of human leukemia (HL-60) cells to arsenic trioxide treatment. Int JEnviron Res Public Health,2006.3(2): p.136-40.
106. Yong, Y., et al., Dichamanetin inhibits cancer cell growth by affectingROS-related signaling components through mitochondrial-mediated apoptosis.Anticancer Res,2013.33(12): p.5349-55.
107. Chen, S., et al., N-acetyl-L-cysteine protects against cadmium-inducedneuronal apoptosis by inhibiting ROS-dependent activation of Akt/mTORpathway in mouse brain. Neuropathol Appl Neurobiol,2013.
108. An, J.J., et al., The ROS/JNK/ATF2pathway mediates selenite-inducedleukemia NB4cell cycle arrest and apoptosis in vitro and in vivo. Cell DeathDis,2013.4: p. e973.
109. Sanchez, Y., et al., Modulation of arsenic trioxide-induced apoptosis bygenistein and functionally related agents in U937human leukaemia cells.Regulation by ROS and mitogen-activated protein kinases. Chem Biol Interact,2009.182(1): p.37-44.
110. Wang, Y., et al., Arsenic induces mitochondria-dependent apoptosis by reactiveoxygen species generation rather than glutathione depletion in Chang humanhepatocytes. Arch Toxicol,2009.83(10): p.899-908.
111. Das, J., et al., Taurine protects rat testes against NaAsO2-induced oxidativestress and apoptosis via mitochondrial dependent and independent pathways.Toxicol Lett,2009.187(3): p.201-10.