進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-1405201118195000
論文名稱(中文) 使用放射線合併三氧化二砷增加對於人類惡性神經膠質瘤和肉瘤細胞抗腫瘤效果之機制探討
論文名稱(英文) Mechanistic study of combination treatment with radiation and arsenic trioxide enhanced antitumor effects in human malignant glioma and sarcoma cells
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 99
學期 2
出版年 100
研究生(中文) 邱惠雯
研究生(英文) Hui-Wen Chiu
學號 s7896106
學位類別 博士
語文別 英文
論文頁數 115頁
口試委員 指導教授-王應然
召集委員-何元順
口試委員-張志欽
口試委員-潘敏雄
口試委員-郭靜娟
中文關鍵字 細胞凋亡  自體吞噬  三氧化二砷  放射線  惡性神經膠質瘤  纖維肉瘤  骨肉瘤  合併治療 
英文關鍵字 apoptosis  autophagy  arsenic trioxide  radiation  malignant gliomas  fibrosarcoma  osteosarcoma  combination therapy 
學科別分類
中文摘要 惡性神經膠質瘤、纖維肉瘤、骨肉瘤主要的治療方法為化學治療、放射線治療以及其他輔助療法,然而這些癌症對於傳統治療方法的治療效果都不佳,因此目前仍需尋找新的治療策略以及藥物。最近發現以前用於治療急性前骨髓性白血病的抗癌藥物三氧化二砷也可以治療某些固態腫瘤,且放射線合併三氧化二砷的治療方式可以增加白血病和固態腫瘤的治療效果。然而,在惡性神經膠質瘤、纖維肉瘤、骨肉瘤中對於放射線合併三氧化二砷的詳細治療機轉目前還未了解。有許多研究發現計畫性細胞死亡(Programmed cell death, PCD)參與在治療癌症的重要機轉中,並且也發現抗癌藥物會誘發第一型(細胞凋亡)和第二型(自體吞噬)計畫性細胞死亡。本篇研究主要利用放射線合併三氧化二砷的治療方式來提升惡性神經膠質瘤(U118-MG)、纖維肉瘤(HT1080)、骨肉瘤(HOS)的治療效果。實驗結果發現合併處理的組別可以經由誘發更多自體吞噬而增加殺死U118-MG神經膠質瘤細胞的效果,而在HT1080纖維肉瘤和HOS骨肉瘤細胞中則是藉由同時誘發自體吞噬和細胞凋亡來增加治療的效果。在U118-MG細胞中合併處理的組別比單獨處理放射線以及三氧化二砷的組別產生更多百分比的細胞分裂延遲的現象,而在HT1080和HOS細胞中則會延長G2/M延遲的時間。另外,我們也發現在HOS細胞中合併處理的組別比單獨處理的組別誘發更多的ROS和增加DNA傷害,而在HT1080細胞中有粒線體膜電位下降的現象。在U118-MG細胞中合併處理的組別經由抑制Akt和活化ERK1/2而誘發更多的自體吞噬;而在HT1080細胞中發現抑制Akt和活化ERK1/2而誘發更多的細胞凋亡和自體吞噬;在HOS細胞中合併處理的組別經由抑制Akt而誘發更多的細胞凋亡和自體吞噬,因此,此研究發現ERK1/2和Akt訊息傳遞可能會同時調控細胞凋亡和自體吞噬。接著我們進一步分析細胞死亡之間的關係,當加入細胞凋亡(Z-VAD)和自體吞噬的抑制劑(3-MA)時發現這兩種方式都可以抑制細胞死亡的百分比。而由活體試驗SCID小鼠打入HT1080細胞株實驗中發現合併處理的組別治療效果明顯高於單獨處理的組別。經由本研究的實驗結果可以更了解放射線合併處理三氧化二砷造成細胞毒性的機制,這樣的研究結果可以幫助設計更有效的治療策略。在此研究中我們發現相同的刺激(放射線合併三氧化二砷)在不同的腫瘤細胞會引發不同的計畫性死亡模式,因此,自體吞噬和細胞凋亡之間的關係在癌症治療中可能扮演重要的角色。合併治療的策略主要是希望可以達到加成或協同殺死癌細胞的效果,本研究結果指出DNA損傷、自體吞噬、細胞凋亡都可能是造成放射線合併處理三氧化二砷具有協同作用的可能機轉。我們希望放射線合併三氧化二砷未來可以當作治療惡性神經膠質瘤、纖維肉瘤、骨肉瘤的新策略,且可以藉由進一步的臨床研究來評估合併治療的確切效果。
英文摘要 Malignant gliomas, fibrosarcoma and osteosarcoma are resistant to many kinds of treatments including chemotherapy, radiotherapy, and other adjuvant therapies. Therefore, new therapeutic strategies and/or new adjuvant drugs still need to be explored. Recently, the anti-cancer drug, arsenic trioxide (ATO), originally used to treat acute promyelocytic leukemia, has drawn attention for the treatment of solid tumors. In addition, it has been reported that combination treatment with ATO and ionizing radiation (IR) is considered the most effective treatment for leukemia and solid tumors. However, the effects and the precise mechanism of combined treatment of ATO and IR against malignant gliomas, fibrosarcoma and osteosarcoma remain unclear. Accumulating evidence indicates that programmed cell death (PCD) is closely related to anti-cancer therapy. Many studies have shown that tumor cells treated with anti-cancer drugs experience the induction of type I PCD, apoptosis, and type II PCD, autophagy. In the present study, we investigated the anti-cancer effects of IR combined with ATO in human malignant glioma (U118-MG), human fibrosarcoma (HT1080) and osteosarcoma cells (HOS). We found that the enhanced cytotoxic effect of IR combined with ATO was through induction of more autophagy in U118-MG cells, whereas the enhanced cytotoxic effect of combined treatment occurred to the increased induction of more autophagy and apoptosis in HT1080 and HOS cells. Combined treatment could induce more mitotic arrest compared to ATO or IR alone in U118-MG cells. IR treatment combined with ATO induced a significantly prolonged G2/M arrest and consequently enhanced cell death in HT1080 and HOS cells. Furthermore, combined treatment showed enhanced ROS generation and DNA damage when compared to treatment with ATO or IR alone in HOS cells and damage of mitochondria membrane potential could be involved in the underlying mechanisms in HT1080 cells. In addition, we also found that the combined treatment-induced autophagy occurred through inhibition of PI3K/Akt and activation of ERK1/2 signaling pathways in U118-MG cells. The enhanced cytotoxic effect of combined treatment occurred to the increased induction of more autophagy and apoptosis through the inhibition of Akt and the activation of ERK1/2 signaling pathways in HT1080 cells. Combined treatment in HOS cells occurred from the increased induction of autophagy and apoptosis through inhibition of the PI3K/Akt signaling pathway. Thus, the cross-talk between the ERK1/2 and the Akt signaling pathways seems to regulate the outcome of autophagy and apoptosis. Furthermore, the combined treatment of HT1080 and HOS cells pre-treated with Z-VAD (a caspase inhibitor) or 3-MA (an autophagy inhibitor) resulted in a significant reduction in cytotoxicity. In in vivo studies, the combination of IR and ATO significantly reduced the tumor volume in SCID mice that had received a subcutaneous injection of HT1080 cells. Knowledge of the mechanism of IR combined with ATO-induced toxicity may help in designing a more effective therapy. In the present study, we found that similar stimuli (IR combined with ATO) can induce different PCD in different tumor cells. Thus, the relationship between autophagy and apoptosis is important for designing new anti-cancer therapy. The aim of combination treatment is to exploit additive or synergistic effects between agents. In this study, we found that DNA damage, autophagy and apoptosis were increased by the combination treatment and could explain part of the observed synergy. The data suggest that a combination of IR and ATO could be a new potential therapeutic strategy for the treatment of malignant gliomas, fibrosarcoma and osteosarcoma. Future clinical studies are awaited to evaluate its therapeutic effect.
論文目次 博士論文口試合格證明.....................................I
中文摘要..............................................II
Abstract............................................IV
致謝.................................................VII
Figure list.........................................XII
Abbreviations.......................................XIII
Publication list....................................XIV
Introduction.........................................1
1. Malignant gliomas............................1
2. Sarcoma......................................1
3. Arsenic trioxide and its anti-tumor cytotoxicity
.............................................2
4. Cell cycle, DNA damage and radiosensitivity of tumor
cells........................................3
5. Apoptosis and autophagy......................5
Objectives...........................................7
Materials and Methods................................8
1. Cell culture and drug treatment..............8
2. Treatment with irradiation and cell viability
assay........................................9
3. Cell cycle analysis..........................9
4. Mitotic index...............................10
5. Clonogenic assay............................10
6. Drug interaction analysis...................11
7. Comet assay.................................11
8. DAPI stain..................................12
9. Determination of apoptosis..................12
10. Analysis of mitochondrial transmembrane
potential...................................12
11. Measurement of ROS production...............13
12. Supravital cell staining with acridine orange for
autophagy detection.........................13
13. Electron microscopy.........................13
14. Immunofluorescence microscopy...............14
15. Western blot analysis.......................14
16. RNA Interference (RNAi).....................15
17. In vivo tumor growth assays using the HT1080 tumor
model in SCID mice..........................15
18. Statistical analysis........................16
Results.............................................17
Part 1. Combination treatment with arsenic trioxide and irradiation enhances autophagic effects in U118-MG cells through increased mitotic arrest and regulation of PI3K/Akt and ERK1/2 signaling pathways.......................17
Part 1. Study design................................17
1.1 Dose-dependent and time course effect of IR on cell cycle distribution in U118-MG cells.................18
1.2 Cytotoxic effects and cell cycle distribution of ATO and IR used alone or in combination on U118-MG cells...............................................18
1.3 Mitotic arrest in U118-MG cells treated with IR and ATO alone or in combination.........................................19
1.4 Measurement of early apoptosis and quantification of mitochondrial membrane potential damage in U118-MG cells...............................................20
1.5 Supravital cell staining with acridine orange using a fluorescence microscope revealed that the induction of acidic vesicle organelles and autophagy are associated with changes in the microtubule-associated protein 1 light chain 3 (LC3).............................................21
1.6 PI3K/Akt and ERK1/2 signaling pathways are involved in ATO- and IR-induced autophagy in U118-MG cells...............................................22
Part 2. Combination treatment with arsenic trioxide and irradiation enhances cell-killing effects in human fibrosarcoma cells in vitro and in vivo through induction of both autophagy and apoptosis........................25
Part 2. Study Design................................25
2.1 Optimal dose and time selection of IR and ATO for treatment of HT1080 cells...........................27
2.2 G2/M arrest and its regulation of HT1080 cells treated with ATO and IR alone or in combination.........................................28
2.3 Measurement of apoptosis in HT1080 cells treated with ATO and IR alone or in combination..................29
2.4 Measurement of autophagy in HT1080 cells treated with ATO and IR alone or in combination..................30
2.5 HT1080 cells undergo autophagy and apoptosis when exposed to IR and ATO...............................32
2.6 Tumor growth in SCID mice was suppressed by IR and ATO.................................................33
Part 3. Synergistic effects of arsenic trioxide and radiation in osteosarcoma cells through the induction of both autophagy and apoptosis........................34
Part 3. Study Design................................34
3.1 Optimal dose and time selection of IR and ATO for treatment of HOS cells..............................35
3.2 IR dose–response survival curves and synergistic cytotoxicity between IR and ATO for HOS cells.......35
3.3 DNA damage determined by the comet assay and measurement of apoptosis in HOS cells treated with ATO and IR alone or in combination..........................36
3.4 Measurement of autophagy in HOS cells treated with ATO and IR alone or in combination..................37
3.5 HOS cells undergo both autophagic and apoptotic cell death when exposed to IR and ATO....................39
3.6 Effects of PEG-catalase on combined treatment-induced cytotoxicity........................................40
Discussion..........................................41
References..........................................54
Figures and table...................................67
Appendix 1..........................................104
Appendix 2..........................................105
Appendix 3..........................................106
Appendix 4..........................................108
Appendix 5..........................................109
Appendix 6..........................................110
Appendix 7..........................................112
Appendix 8..........................................113
Appendix 9..........................................114
參考文獻 Aldridge, D. R., and Radford, I. R. (1998). Explaining differences in sensitivity to killing by ionizing radiation between human lymphoid cell lines. Cancer Res 58, 2817-2824.
Amaravadi, R. K., Yu, D., Lum, J. J., Bui, T., Christophorou, M. A., Evan, G. I., Thomas-Tikhonenko, A., and Thompson, C. B. (2007). Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117, 326-336.
Antonsson, B., Montessuit, S., Sanchez, B., and Martinou, J. C. (2001). Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. J Biol Chem 276, 11615-11623.
Aoki, H., Takada, Y., Kondo, S., Sawaya, R., Aggarwal, B. B., and Kondo, Y. (2007). Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 72, 29-39.
Arico, S., Petiot, A., Bauvy, C., Dubbelhuis, P. F., Meijer, A. J., Codogno, P., and Ogier-Denis, E. (2001). The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 276, 35243-35246.
Bartek, J., Bartkova, J., and Lukas, J. (2007). DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 26, 7773-7779.
Bhalla, K. N. (2003). Microtubule-targeted anticancer agents and apoptosis. Oncogene 22, 9075-9086.
Bitomsky, N., and Hofmann, T. G. (2009). Apoptosis and autophagy: Regulation of apoptosis by DNA damage signalling - roles of p53, p73 and HIPK2. FEBS J 276, 6074-6083.
Bjorkoy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., Stenmark, H., and Johansen, T. (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171, 603-614.
Blommaart, E. F., Luiken, J. J., and Meijer, A. J. (1997). Autophagic proteolysis: control and specificity. Histochem J 29, 365-385.
Bommareddy, A., Hahm, E. R., Xiao, D., Powolny, A. A., Fisher, A. L., Jiang, Y., and Singh, S. V. (2009). Atg5 regulates phenethyl isothiocyanate-induced autophagic and apoptotic cell death in human prostate cancer cells. Cancer Res 69, 3704-3712.
Bras, M., Queenan, B., and Susin, S. A. (2005). Programmed cell death via mitochondria: different modes of dying. Biochemistry (Mosc) 70, 231-239.
Burdak-Rothkamm, S., and Prise, K. M. (2009). New molecular targets in radiotherapy: DNA damage signalling and repair in targeted and non-targeted cells. Eur J Pharmacol 625, 151-155.
Bursch, W., Ellinger, A., Gerner, C., Frohwein, U., and Schulte-Hermann, R. (2000). Programmed cell death (PCD). Apoptosis, autophagic PCD, or others? Annals of the New York Academy of Sciences 926, 1-12.
Cai, X., Yu, Y., Huang, Y., Zhang, L., Jia, P. M., Zhao, Q., Chen, Z., Tong, J. H., Dai, W., and Chen, G. Q. (2003). Arsenic trioxide-induced mitotic arrest and apoptosis in acute promyelocytic leukemia cells. Leukemia 17, 1333-1337.
Carew, J. S., Nawrocki, S. T., Kahue, C. N., Zhang, H., Yang, C., Chung, L., Houghton, J. A., Huang, P., Giles, F. J., and Cleveland, J. L. (2007). Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 110, 313-322.
Cecchetto, G., Carli, M., Alaggio, R., Dall'Igna, P., Bisogno, G., Scarzello, G., Zanetti, I., Durante, G., Inserra, A., Siracusa, F., and Guglielmi, M. (2001). Fibrosarcoma in pediatric patients: results of the Italian Cooperative Group studies (1979-1995). J Surg Oncol 78, 225-231.
Chen, G. Q., Shi, X. G., Tang, W., Xiong, S. M., Zhu, J., Cai, X., Han, Z. G., Ni, J. H., Shi, G. Y., Jia, P. M., et al. (1997). Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89, 3345-3353.
Chen, T., and Wong, Y. S. (2008). Selenocystine induces S-phase arrest and apoptosis in human breast adenocarcinoma MCF-7 cells by modulating ERK and Akt phosphorylation. J Agric Food Chem 56, 10574-10581.
Cheng, T. J., Wang, Y. J., Kao, W. W., Chen, R. J., and Ho, Y. S. (2007). Protection against arsenic trioxide-induced autophagic cell death in U118 human glioma cells by use of lipoic acid. Food Chem Toxicol 45, 1027-1038.
Chiu, H. W., Ho, S. Y., Guo, H. R., and Wang, Y. J. (2009). Combination treatment with arsenic trioxide and irradiation enhances autophagic effects in U118-MG cells through increased mitotic arrest and regulation of PI3K/Akt and ERK1/2 signaling pathways. Autophagy 5, 472-483.
Chiu, H. W., Lin, J. H., Chen, Y. A., Ho, S. Y., and Wang, Y. J. (2010). Combination treatment with arsenic trioxide and irradiation enhances cell-killing effects in human fibrosarcoma cells in vitro and in vivo through induction of both autophagy and apoptosis. Autophagy 6, 353-365.
Chou, T. C., and Talalay, P. (1984). Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22, 27-55.
Chun, Y.-J., Park, I.-C., Park, M.-J., Woo, S.-H., Hong, S.-I., Chung, H. Y., Kim, T.-H., Lee, Y.-S., Rhee, C.-H., and Lee, S.-J. (2002a). Enhancement of radiation response in human cervical cancer cells in vitro and in vivo by arsenic trioxide (As2O3). FEBS Lett 519, 195-200.
Chun, Y. J., Park, I. C., Park, M. J., Woo, S. H., Hong, S. I., Chung, H. Y., Kim, T. H., Lee, Y. S., Rhee, C. H., and Lee, S. J. (2002b). Enhancement of radiation response in human cervical cancer cells in vitro and in vivo by arsenic trioxide (As2O3). FEBS Lett 519, 195-200.
Cohen, I., Castedo, M., and Kroemer, G. (2002). Tantalizing Thanatos: unexpected links in death pathways. Trends Cell Biol 12, 293-295.
Colosetti, P., Puissant, A., Robert, G., Luciano, F., Jacquel, A., Gounon, P., Cassuto, J. P., and Auberger, P. (2009). Autophagy is an important event for megakaryocytic differentiation of the chronic myelogenous leukemia K562 cell line. Autophagy 5.
Corcelle, E., Nebout, M., Bekri, S., Gauthier, N., Hofman, P., Poujeol, P., Fenichel, P., and Mograbi, B. (2006). Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. Cancer Res 66, 6861-6870.
Dagda, R. K., Zhu, J., Kulich, S. M., and Chu, C. T. (2008). Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress: implications for Parkinson's disease. Autophagy 4, 770-782.
Dai, J., Weinberg, R. S., Waxman, S., and Jing, Y. (1999). Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood 93, 268-277.
Doherty, S. C., McKeown, S. R., McKelvey-Martin, V., Downes, C. S., Atala, A., Yoo, J. J., Simpson, D. A., and Kaufmann, W. K. (2003). Cell cycle checkpoint function in bladder cancer. J Natl Cancer Inst 95, 1859-1868.
Eisenberg-Lerner, A., Bialik, S., Simon, H. U., and Kimchi, A. (2009). Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16, 966-975.
Ellington, A. A., Berhow, M. A., and Singletary, K. W. (2006). Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells. Carcinogenesis 27, 298-306.
Glick, D., Barth, S., and Macleod, K. F. (2010). Autophagy: cellular and molecular mechanisms. J Pathol 221, 3-12.
Gong, J., Traganos, F., and Darzynkiewicz, Z. (1995). Discrimination of G2 and mitotic cells by flow cytometry based on different expression of cyclins A and B1. Exp Cell Res 220, 226-231.
Gozuacik, D., and Kimchi, A. (2004). Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23, 2891-2906.
Grander, D., Kharaziha, P., Laane, E., Pokrovskaja, K., and Panaretakis, T. (2009). Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignancies. Autophagy 5.
Green, N., French, S., Rodriquez, G., Hays, M., and Fingerhut, A. (1969). Radiation-induced delayed union of fractures. Radiology 93, 635-641.
Griffin, R., Lee, S., Rood, K., Stewart, M., Lyons, J., Lew, Y., Park, H., and Song, C. (2000). Use of arsenic trioxide as an antivascular and thermosensitizing agent in solid tumors. Neoplasia (New York) 2, 555-560.
Grossman, S. A., Ye, X., Piantadosi, S., Desideri, S., Nabors, L. B., Rosenfeld, M., and Fisher, J. (2010). Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 16, 2443-2449.
Gunn, J. M., Clark, M. G., Knowles, S. E., Hopgood, M. F., and Ballard, F. J. (1977). Reduced rates of proteolysis in transformed cells. Nature 266, 58-60.
Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y., and Mills, G. B. (2005). Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4, 988-1004.
Higginbottom, K., Jahnke, U., Newland, A. C., Cotter, F. E., and Allen, P. D. (2007). New alternative phosphorylation sites on the cyclin dependent kinase 1/cyclin a complex in p53-deficient human cells treated with etoposide: possible association with etoposide-induced apoptosis. Apoptosis 12, 1847-1855.
Ho, S. Y., Chen, W. C., Chiu, H. W., Lai, C. S., Guo, H. R., and Wang, Y. J. (2009). Combination treatment with arsenic trioxide and irradiation enhances apoptotic effects in U937 cells through increased mitotic arrest and ROS generation. Chem Biol Interact 179, 304-313.
Ho, Y. S., Wang, Y. J., and Lin, J. K. (1996). Induction of p53 and p21/WAF1/CIP1 expression by nitric oxide and their association with apoptosis in human cancer cells. Mol Carcinog 16, 20-31.
Howell, B. J., Hoffman, D. B., Fang, G., Murray, A. W., and Salmon, E. D. (2000). Visualization of Mad2 dynamics at kinetochores, along spindle fibers, and at spindle poles in living cells. J Cell Biol 150, 1233-1250.
Hoyer-Hansen, M., and Jaattela, M. (2008). Autophagy: an emerging target for cancer therapy. Autophagy 4, 574-580.
Hsu, K. F., Wu, C. L., Huang, S. C., Wu, C. M., Hsiao, J. R., Yo, Y. T., Chen, Y. H., Shiau, A. L., and Chou, C. Y. (2009). Cathepsin L mediates resveratrol-induced autophagy and apoptotic cell death in cervical cancer cells. Autophagy 5, 451-460.
Iliakis, G., Wang, Y., Guan, J., and Wang, H. (2003). DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene 22, 5834-5847.
Ito, H., Daido, S., Kanzawa, T., Kondo, S., and Kondo, Y. (2005). Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells. Int J Oncol 26, 1401-1410.
Jereczek-Fossa, B. A., and Orecchia, R. (2002). Radiotherapy-induced mandibular bone complications. Cancer Treat Rev 28, 65-74.
Kang, Y. H., and Lee, S. J. (2008). Role of p38 MAPK and JNK in enhanced cervical cancer cell killing by the combination of arsenic trioxide and ionizing radiation. Oncol Rep 20, 637-643.
Kanzawa, T., Kondo, Y., Ito, H., Kondo, S., and Germano, I. (2003). Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res 63, 2103-2108.
Kanzawa, T., Zhang, L., Xiao, L., Germano, I. M., Kondo, Y., and Kondo, S. (2005). Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene 24, 980-991.
Khanna, K. K., and Jackson, S. P. (2001). DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27, 247-254.
Kim, E. H., Sohn, S., Kwon, H. J., Kim, S. U., Kim, M. J., Lee, S. J., and Choi, K. S. (2007). Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. Cancer Res 67, 6314-6324.
Kim, K. W., Hwang, M., Moretti, L., Jaboin, J. J., Cha, Y. I., and Lu, B. (2008). Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. Autophagy 4, 659-668.
Kim, R., Emi, M., Tanabe, K., Uchida, Y., and Arihiro, K. (2006). The role of apoptotic or nonapoptotic cell death in determining cellular response to anticancer treatment. Eur J Surg Oncol 32, 269-277.
Kirkegaard, K., Taylor, M. P., and Jackson, W. T. (2004). Cellular autophagy: surrender, avoidance and subversion by microorganisms. Nat Rev Microbiol 2, 301-314.
Kisen, G. O., Tessitore, L., Costelli, P., Gordon, P. B., Schwarze, P. E., Baccino, F. M., and Seglen, P. O. (1993). Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. Carcinogenesis 14, 2501-2505.
Klionsky, D., and Emr, S. (2000). Autophagy as a regulated pathway of cellular degradation. Science 290, 1717-1721.
Klionsky, D. J., Cregg, J. M., Dunn, W. A., Emr, S. D., Sakai, Y., Sandoval, I. V., Sibirny, A., Subramani, S., Thumm, M., Veenhuis, M., and Ohsumi, Y. (2003). A unified nomenclature for yeast autophagy-related genes. Dev Cell 5, 539-545.
Kondo, Y., Kanzawa, T., Sawaya, R., and Kondo, S. (2005). The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5, 726-734.
Koul, D., Shen, R., Kim, Y. W., Kondo, Y., Lu, Y., Bankson, J., Ronen, S. M., Kirkpatrick, D. L., Powis, G., and Yung, W. K. (2010). Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol 12, 559-565.
Kroeger, K. M., Muhammad, A. K., Baker, G. J., Assi, H., Wibowo, M. K., Xiong, W., Yagiz, K., Candolfi, M., Lowenstein, P. R., and Castro, M. G. (2010). Gene therapy and virotherapy: novel therapeutic approaches for brain tumors. Discov Med 10, 293-304.
Kumar, P., Gao, Q., Ning, Y., Wang, Z., Krebsbach, P. H., and Polverini, P. J. (2008). Arsenic trioxide enhances the therapeutic efficacy of radiation treatment of oral squamous carcinoma while protecting bone. Mol Cancer Ther 7, 2060-2069.
Lee, D. H., Park, T., and Kim, H. W. (2006). Induction of apoptosis by disturbing mitochondrial-membrane potential and cleaving PARP in Jurkat T cells through treatment with acetoxyscirpenol mycotoxins. Biol Pharm Bull 29, 648-654.
Levine, A. J. (1997). p53, the cellular gatekeeper for growth and division. Cell 88, 323-331.
Lew, Y. S., Kolozsvary, A., Brown, S. L., and Kim, J. H. (2002). Synergistic interaction with arsenic trioxide and fractionated radiation in locally advanced murine tumor. Cancer Res 62, 4202-4205.
Li, Y. M., and Broome, J. D. (1999). Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells. Cancer Res 59, 776-780.
Liang, X. Q., Cao, E. H., Zhang, Y., and Qin, J. F. (2003). P53-induced gene 11 (PIG11) involved in arsenic trioxide-induced apoptosis in human gastric cancer MGC-803 cells. Oncol Rep 10, 1265-1269.
Ling, Y. H., Jiang, J. D., Holland, J. F., and Perez-Soler, R. (2002). Arsenic trioxide produces polymerization of microtubules and mitotic arrest before apoptosis in human tumor cell lines. Mol Pharmacol 62, 529-538.
Liu, B., Cheng, Y., Zhang, B., Bian, H. J., and Bao, J. K. (2009). Polygonatum cyrtonema lectin induces apoptosis and autophagy in human melanoma A375 cells through a mitochondria-mediated ROS-p38-p53 pathway. Cancer Lett 275, 54-60.
Liu, J. D., Wang, Y. J., Chen, C. H., Yu, C. F., Chen, L. C., Lin, J. K., Liang, Y. C., Lin, S. Y., and Ho, Y. S. (2003). Molecular mechanisms of G0/G1 cell-cycle arrest and apoptosis induced by terfenadine in human cancer cells. Mol Carcinog 37, 39-50.
Liu, J. J., Lin, M., Yu, J. Y., Liu, B., and Bao, J. K. (2011). Targeting apoptotic and autophagic pathways for cancer therapeutics. Cancer Lett 300, 105-114.
Lockshin, R. A., and Zakeri, Z. (2004). Apoptosis, autophagy, and more. Int J Biochem Cell Biol 36, 2405-2419.
Ma, D. C., Sun, Y. H., Chang, K. Z., Ma, X. F., Huang, S. L., Bai, Y. H., Kang, J., Liu, Y. G., and Chu, J. J. (1998). Selective induction of apoptosis of NB4 cells from G2+M phase by sodium arsenite at lower doses. Eur J Haematol 61, 27-35.
Maeda, H., Hori, S., Nishitoh, H., Ichijo, H., Ogawa, O., Kakehi, Y., and Kakizuka, A. (2001). Tumor growth inhibition by arsenic trioxide (As2O3) in the orthotopic metastasis model of androgen-independent prostate cancer. Cancer Res 61, 5432-5440.
Mamelak, A. N., and Jacoby, D. B. (2007). Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601). Expert Opin Drug Deliv 4, 175-186.
Matsui, Y., Takagi, H., Qu, X., Abdellatif, M., Sakoda, H., Asano, T., Levine, B., and Sadoshima, J. (2007). Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100, 914-922.
McArt, D. G., McKerr, G., Saetzler, K., Howard, C. V., Downes, C. S., and Wasson, G. R. (2010). Comet sensitivity in assessing DNA damage and repair in different cell cycle stages. Mutagenesis 25, 299-303.
McCabe, M. J., Jr., Singh, K. P., Reddy, S. A., Chelladurai, B., Pounds, J. G., Reiners, J. J., Jr., and States, J. C. (2000). Sensitivity of myelomonocytic leukemia cells to arsenite-induced cell cycle disruption, apoptosis, and enhanced differentiation is dependent on the inter-relationship between arsenic concentration, duration of treatment, and cell cycle phase. J Pharmacol Exp Ther 295, 724-733.
McCollum, G., Keng, P. C., States, J. C., and McCabe, M. J., Jr. (2005). Arsenite delays progression through each cell cycle phase and induces apoptosis following G2/M arrest in U937 myeloid leukemia cells. J Pharmacol Exp Ther 313, 877-887.
McCubrey, J. A., Lahair, M. M., and Franklin, R. A. (2006). OSU-03012 in the treatment of glioblastoma. Mol Pharmacol 70, 437-439.
McDonnell, T. J., Meyn, R. E., and Robertson, L. E. (1995). Implications of apoptotic cell death regulation in cancer therapy. Semin Cancer Biol 6, 53-60.
Meijer, A. J., and Codogno, P. (2004). Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol 36, 2445-2462.
Mizushima, N., and Yoshimori, T. (2007). How to interpret LC3 immunoblotting. Autophagy 3, 542-545.
Moon, D. O., Lee, K. J., Choi, Y. H., and Kim, G. Y. (2007). Beta-sitosterol-induced-apoptosis is mediated by the activation of ERK and the downregulation of Akt in MCA-102 murine fibrosarcoma cells. Int Immunopharmacol 7, 1044-1053.
Morgan, D. O. (1995). Principles of CDK regulation. Nature 374, 131-134.
Moscat, J., and Diaz-Meco, M. T. (2009). p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 137, 1001-1004.
Nakamura, Y., Yogosawa, S., Izutani, Y., Watanabe, H., Otsuji, E., and Sakai, T. (2009). A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Mol Cancer 8, 100.
Nakasu, S., Nakasu, Y., Nioka, H., Nakajima, M., and Handa, J. (1994). bcl-2 protein expression in tumors of the central nervous system. Acta Neuropathol (Berl) 88, 520-526.
Narvaez, C. J., and Welsh, J. (2001). Role of mitochondria and caspases in vitamin D-mediated apoptosis of MCF-7 breast cancer cells. J Biol Chem 276, 9101-9107.
Ng, G., and Huang, J. (2005). The significance of autophagy in cancer. Mol Carcinog 43, 183-187.
Ning, S., and Knox, S. J. (2004). Increased cure rate of glioblastoma using concurrent therapy with radiotherapy and arsenic trioxide. Int J Radiat Oncol Biol Phys 60, 197-203.
Ning, S., and Knox, S. J. (2006). Optimization of combination therapy of arsenic trioxide and fractionated radiotherapy for malignant glioma. Int J Radiat Oncol Biol Phys 65, 493-498.
Ogier-Denis, E., and Codogno, P. (2003). Autophagy: a barrier or an adaptive response to cancer. Biochim Biophys Acta 1603, 113-128.
Ogier-Denis, E., Couvineau, A., Maoret, J. J., Houri, J. J., Bauvy, C., De Stefanis, D., Isidoro, C., Laburthe, M., and Codogno, P. (1995). A heterotrimeric Gi3-protein controls autophagic sequestration in the human colon cancer cell line HT-29. J Biol Chem 270, 13-16.
Ogier-Denis, E., Pattingre, S., El Benna, J., and Codogno, P. (2000). Erk1/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells. J Biol Chem 275, 39090-39095.
Ohneseit, P. A., Prager, D., Kehlbach, R., and Rodemann, H. P. (2005). Cell cycle effects of topotecan alone and in combination with irradiation. Radiother Oncol 75, 237-245.
Oltvai, Z. N., Milliman, C. L., and Korsmeyer, S. J. (1993). Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74, 609-619.
Orbach, D., Rey, A., Cecchetto, G., Oberlin, O., Casanova, M., Thebaud, E., Scopinaro, M., Bisogno, G., Carli, M., and Ferrari, A. (2009). Infantile Fibrosarcoma: Management Based on the European Experience. J Clin Oncol.
Osborne, C. K., Coronado, E. B., and Robinson, J. P. (1987). Human breast cancer in the athymic nude mouse: cytostatic effects of long-term antiestrogen therapy. Eur J Cancer Clin Oncol 23, 1189-1196.
Paglin, S., Hollister, T., Delohery, T., Hackett, N., McMahill, M., Sphicas, E., Domingo, D., and Yahalom, J. (2001). A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61, 439-444.
Pandha, H. S., Heinemann, L., Simpson, G. R., Melcher, A., Prestwich, R., Errington, F., Coffey, M., Harrington, K. J., and Morgan, R. (2009). Synergistic effects of oncolytic reovirus and cisplatin chemotherapy in murine malignant melanoma. Clin Cancer Res 15, 6158-6166.
Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J. A., Outzen, H., Overvatn, A., Bjorkoy, G., and Johansen, T. (2007). p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282, 24131-24145.
Park, M. J., Lee, J. Y., Kwak, H. J., Park, C. M., Lee, H. C., Woo, S. H., Jin, H. O., Han, C. J., An, S., Lee, S. H., et al. (2005). Arsenic trioxide (As2O3) inhibits invasion of HT1080 human fibrosarcoma cells: role of nuclear factor-kappaB and reactive oxygen species. J Cell Biochem 95, 955-969.
Pattingre, S., Bauvy, C., and Codogno, P. (2003). Amino acids interfere with the ERK1/2-dependent control of macroautophagy by controlling the activation of Raf-1 in human colon cancer HT-29 cells. J Biol Chem 278, 16667-16674.
Peng, P. L., Kuo, W. H., Tseng, H. C., and Chou, F. P. (2008). Synergistic tumor-killing effect of radiation and berberine combined treatment in lung cancer: the contribution of autophagic cell death. Int J Radiat Oncol Biol Phys 70, 529-542.
Qian, W., Liu, J., Jin, J., Ni, W., and Xu, W. (2007). Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. Leuk Res 31, 329-339.
Reggiori, F., and Klionsky, D. J. (2002). Autophagy in the eukaryotic cell. Eukaryot Cell 1, 11-21.
Ricci, M. S., and Zong, W. X. (2006). Chemotherapeutic approaches for targeting cell death pathways. Oncologist 11, 342-357.
Rieger, L., Weller, M., Bornemann, A., Schabet, M., Dichgans, J., and Meyermann, R. (1998). BCL-2 family protein expression in human malignant glioma: a clinical-pathological correlative study. J Neurol Sci 155, 68-75.
Roboz, G. J., Dias, S., Lam, G., Lane, W. J., Soignet, S. L., Warrell, R. P., Jr., and Rafii, S. (2000). Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood 96, 1525-1530.
Rodriguez-Enriquez, S., He, L., and Lemasters, J. J. (2004). Role of mitochondrial permeability transition pores in mitochondrial autophagy. Int J Biochem Cell Biol 36, 2463-2472.
Rosenfeldt, M. T., and Ryan, K. M. (2009). The role of autophagy in tumour development and cancer therapy. Expert Rev Mol Med 11, e36.
Sampath, D., and Plunkett, W. (2001). Design of new anticancer therapies targeting cell cycle checkpoint pathways. Curr Opin Oncol 13, 484-490.
Sarbassov, D. D., Guertin, D. A., Ali, S. M., and Sabatini, D. M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098-1101.
Sasi, N., Hwang, M., Jaboin, J., Csiki, I., and Lu, B. (2009). Regulated cell death pathways: new twists in modulation of BCL2 family function. Mol Cancer Ther 8, 1421-1429.
Shen, Z. X., Chen, G. Q., Ni, J. H., Li, X. S., Xiong, S. M., Qiu, Q. Y., Zhu, J., Tang, W., Sun, G. L., Yang, K. Q., et al. (1997). Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89, 3354-3360.
Skubitz, K. M., and D'Adamo, D. R. (2007). Sarcoma. Mayo Clin Proc 82, 1409-1432.
Smits, V. A., and Medema, R. H. (2001). Checking out the G(2)/M transition. Biochim Biophys Acta 1519, 1-12.
Soignet, S. L., Frankel, S. R., Douer, D., Tallman, M. S., Kantarjian, H., Calleja, E., Stone, R. M., Kalaycio, M., Scheinberg, D. A., Steinherz, P., et al. (2001). United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19, 3852-3860.
Song, K. S., Kim, J. S., Yun, E. J., Kim, Y. R., Seo, K. S., Park, J. H., Jung, Y. J., Park, J. I., Kweon, G. R., Yoon, W. H., et al. (2008). Rottlerin induces autophagy and apoptotic cell death through a PKC-delta-independent pathway in HT1080 human fibrosarcoma cells: the protective role of autophagy in apoptosis. Autophagy 4, 650-658.
Su, L. N., and Little, J. B. (1993). Prolonged cell cycle delay in radioresistant human cell lines transfected with activated ras oncogene and/or simian virus 40 T-antigen. Radiat Res 133, 73-79.
Sumi, D., Shinkai, Y., and Kumagai, Y. (2010). Signal transduction pathways and transcription factors triggered by arsenic trioxide in leukemia cells. Toxicol Appl Pharmacol 244, 385-392.
Sun, Y., and Peng, Z. L. (2009). Programmed cell death and cancer. Postgrad Med J 85, 134-140.
Susin, S. A., Zamzami, N., Castedo, M., Hirsch, T., Marchetti, P., Macho, A., Daugas, E., Geuskens, M., and Kroemer, G. (1996). Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J Exp Med 184, 1331-1341.
Sy, L. K., Yan, S. C., Lok, C. N., Man, R. Y., and Che, C. M. (2008). Timosaponin A-III induces autophagy preceding mitochondria-mediated apoptosis in HeLa cancer cells. Cancer Res 68, 10229-10237.
Takeuchi, H., Kondo, Y., Fujiwara, K., Kanzawa, T., Aoki, H., Mills, G. B., and Kondo, S. (2005). Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 65, 3336-3346.
Traganos, F., and Darzynkiewicz, Z. (1994). Lysosomal proton pump activity: supravital cell staining with acridine orange differentiates leukocyte subpopulations. Methods Cell Biol 41, 185-194.
Verheij, M., Vens, C., and van Triest, B. (2010). Novel therapeutics in combination with radiotherapy to improve cancer treatment: Rationale, mechanisms of action and clinical perspective. Drug Resist Updat 3, 29-43.
Vorotnikova, E., Rosenthal, R. A., Tries, M., Doctrow, S. R., and Braunhut, S. J. (2010). Novel synthetic SOD/catalase mimetics can mitigate capillary endothelial cell apoptosis caused by ionizing radiation. Radiat Res 173, 748-759.
Vuky, J., Yu, R., Schwartz, L., and Motzer, R. J. (2002). Phase II trial of arsenic trioxide in patients with metastatic renal cell carcinoma. Invest New Drugs 20, 327-330.
Wahl, G. M., and Carr, A. M. (2001). The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nat Cell Biol 3, E277-286.
Wang, Z. H., Xu, L., Duan, Z. L., Zeng, L. Q., Yan, N. H., and Peng, Z. L. (2007). Beclin 1-mediated macroautophagy involves regulation of caspase-9 expression in cervical cancer HeLa cells. Gynecol Oncol 107, 107-113.
Watcharasit, P., Thiantanawat, A., and Satayavivad, J. (2008). GSK3 promotes arsenite-induced apoptosis via facilitation of mitochondria disruption. J Appl Toxicol 28, 466-474.
Withers, H. R., Mason, K., Reid, B. O., Dubravsky, N., Barkley, H. T., Jr., Brown, B. W., and Smathers, J. B. (1974). Response of mouse intestine to neutrons and gamma rays in relation to dose fractionation and division cycle. Cancer 34, 39-47.
Xie, X. K., Yang, D. S., Ye, Z. M., and Tao, H. M. (2009). Enhancement effect of adenovirus-mediated antisense c-myc and caffeine on the cytotoxicity of cisplatin in osteosarcoma cell lines. Chemotherapy 55, 433-440.
Xu, Y., Kim, S. O., Li, Y., and Han, J. (2006). Autophagy contributes to caspase-independent macrophage cell death. J Biol Chem 281, 19179-19187.
Yan, C. H., Liang, Z. Q., Gu, Z. L., Yang, Y. P., Reid, P., and Qin, Z. H. (2006). Contributions of autophagic and apoptotic mechanisms to CrTX-induced death of K562 cells. Toxicon 47, 521-530.
Yan, C. H., Yang, Y. P., Qin, Z. H., Gu, Z. L., Reid, P., and Liang, Z. Q. (2007). Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells. Acta Pharmacol Sin 28, 540-548.
Yao, K. C., Komata, T., Kondo, Y., Kanzawa, T., Kondo, S., and Germano, I. M. (2003). Molecular response of human glioblastoma multiforme cells to ionizing radiation: cell cycle arrest, modulation of the expression of cyclin-dependent kinase inhibitors, and autophagy. J Neurosurg 98, 378-384.
Yih, L. H., Hsueh, S. W., Luu, W. S., Chiu, T. H., and Lee, T. C. (2005). Arsenite induces prominent mitotic arrest via inhibition of G2 checkpoint activation in CGL-2 cells. Carcinogenesis 26, 53-63.
Yokoyama, T., Miyazawa, K., Naito, M., Toyotake, J., Tauchi, T., Itoh, M., Yuo, A., Hayashi, Y., Georgescu, M. M., Kondo, Y., et al. (2008). Vitamin K2 induces autophagy and apoptosis simultaneously in leukemia cells. Autophagy 4, 629-640.
Yu, L., Alva, A., Su, H., Dutt, P., Freundt, E., Welsh, S., Baehrecke, E. H., and Lenardo, M. J. (2004). Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500-1502.
Yu, L., Wan, F., Dutta, S., Welsh, S., Liu, Z., Freundt, E., Baehrecke, E. H., and Lenardo, M. (2006). Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci U S A 103, 4952-4957.
Zhang, H., Kong, X., Kang, J., Su, J., Li, Y., Zhong, J., and Sun, L. (2009a). Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells. Toxicol Sci 110, 376-388.
Zhang, H., Kong, X., Kang, J., Su, J., Li, Y., Zhong, J., and Sun, L. (2009b). Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells. Toxicol Sci.
Zhang, Y., Wu, Y., Wu, D., Tashiro, S., Onodera, S., and Ikejima, T. (2009c). NF-kappab facilitates oridonin-induced apoptosis and autophagy in HT1080 cells through a p53-mediated pathway. Arch Biochem Biophys 489, 25-33.
Zhao, S., Tsuchida, T., Kawakami, K., Shi, C., and Kawamoto, K. (2002). Effect of As2O3 on cell cycle progression and cyclins D1 and B1 expression in two glioblastoma cell lines differing in p53 status. Int J Oncol 21, 49-55.
Zhao, S., Zhang, X., Zhang, J., Zou, H., Liu, Y., Dong, X., and Sun, X. (2008). Intravenous administration of arsenic trioxide encapsulated in liposomes inhibits the growth of C6 gliomas in rat brains. J Chemother 20, 253-262.
Zhu, X. H., Shen, Y. L., Jing, Y. K., Cai, X., Jia, P. M., Huang, Y., Tang, W., Shi, G. Y., Sun, Y. P., Dai, J., et al. (1999). Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J Natl Cancer Inst 91, 772-778.
Zhuang, W., Qin, Z., and Liang, Z. (2009). The role of autophagy in sensitizing malignant glioma cells to radiation therapy. Acta Biochim Biophys Sin (Shanghai) 41, 341-351.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2014-06-09起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw