小分子化合物诱导人肺腺癌A549细胞凋亡机理研究
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摘要
小分子化合物诱导人肺腺癌A549细胞凋亡机理研究
研究目的
近年来,肺癌死亡率居于各种恶性肿瘤之首位,其中肺腺癌最常见并且其发病率最高。由于肿瘤发生和生长的主要原因在于细胞凋亡受到抑制,因此,诱导肺腺癌细胞凋亡是治疗肺腺癌的重要措施,也是降低肺癌死亡率的有力手段之一。本文以人肺腺癌A549细胞系为例,利用化学遗传学这一新兴技术平台,筛选有效的诱导肺腺癌细胞凋亡的小分子化合物并研究其凋亡诱导分子机制,为进一步研究小分子凋亡诱导剂的特异性靶蛋白这一后续工作奠定基础,同时为开发新型的肺腺癌治疗药物提供理论依据。
研究内容
1.对小分子化合物进行初步筛选
2.鉴定小分子化合物对A549细胞的凋亡诱导作用
3.研究小分子化合物诱导A549细胞凋亡的分子机制
研究方法
1.MTT法检测细胞存活率,由此对小分子化合物进行初步筛选
2.倒置相差显微镜观察细胞形态变化
3.LDH(乳酸脱氢酶)检测细胞是否出现坏死
4.吖啶橙染色结合激光扫描共聚焦显微镜观察,检测细胞核凝集
5.TUNEL染色检测DNA片段化和凋亡率
6.荧光探针DCHF检测ROS表达水平
7.利用TMRM染色检测细胞线粒体膜电位变化[Falchi et al,2005]
8.免疫荧光化学法检测膜整连蛋白β4的表达
研究结果
1苯并噁嗪酮衍生物对A549细胞的生长抑制作用
1.1 MTT检测结果表明,在24h-48h内,5种苯并嗯嗪酮衍生物(1-5~#)均能抑制A549细胞的生长,且其抑制作用呈现时间和浓度依赖性。
1.2倒置相差显微镜观察细胞形态发现:200μM苯并嗯嗪酮衍生物(1-5~#)分别处理A549细胞24h,细胞明显缩小,有的细胞变圆。
2二茂铁基吡唑并哌嗪化合物对A549细胞的凋亡诱导作用
2.1 MTT检测结果表明,在24h-48h内,6种二茂铁基吡唑并哌嗪化合物(8a-8f)均能显著降低A549细胞的存活率并且其作用效果呈现时间和浓度依赖性。
2.2倒置相差显微镜观察细胞形态发现:8d-8f各20μM分别处理A549细胞24h-48h,细胞呈现典型的凋亡形态学特征。
2.3吖啶橙染色结合激光扫描共聚焦显微镜检测细胞核片段化,发现:20μM8d-8f分别处理A549细胞48h时,细胞核固缩、染色质凝集、凋亡小体清晰可见。
2.4 LDH检测发现:8d-8f各20μM分别处理A549细胞48h时,与对照组细胞相比,培养液中LDH酶活浓度未发生显著性变化(P＞0.05)。
2.5 TUNEL染色发现,8d-8f各20μM分别处理A549细胞48h,TUNEL染色阳性率显著升高(P＜0.01)。
2.6使用荧光探针DCHF检测细胞内ROS水平的变化,结果发现,8d-8f各20μM分别处理A549细胞48h时,细胞内的ROS水平显著升高(P＜0.01)。
2.7利用TMRM染色检测细胞线粒体膜电位的变化,结果显示,8d-8f各20μM分别处理A549细胞48h时,细胞内的线粒体膜电位显著升高(P＜0.01)。
2.8免疫细胞化学检测发现,8d-8f各20μM分别处理A549细胞48h时,膜整连蛋白β4的水平显著升高(P＜0.01)。
结论
1.小分子化合物初步筛选结果表明,5种苯并噁嗪酮衍生物对A549细胞生长均有抑制作用,其中2~#、3~#和5~#化合物的抑制作用比较明显。
2.MTT初步筛选结果显示,6种二茂铁基吡唑并哌嗪化合物(8a-8f)对A549细胞增殖均有抑制作用,但其增殖抑制能力不同,其中8d、8e、8f三种小分子化合物增殖抑制能力较强,因此选取该三种小分子继续研究其对A549细胞的作用及其分子机制。
3.8d、8e、8f三种小分子化合物20μM均能诱导A549细胞凋亡,而该凋亡诱导作用可能是通过提高ROS水平和影响线粒体膜电位来实现的。
4.在8d、8e、8f三种小分子化合物诱导A549细胞凋亡的过程中,膜整连蛋白β4的表达水平升高,说明膜整连蛋白β4可能是该类小分子化合物诱导A549细胞凋亡途径中的一个重要因子。
INVESTIGATION OF SMALL MOLECULE-INDUCED APOPTOSIS AND THE MOLECULAR MECHANISMS IN A549 HUMAN LUNG CANCER CELLS
In recent years,lung cancer is the leading category of cancer threatening the health of the people in many countries,lung cancer mortality stands the first within all kinds of cancer death.Moreover,among all types of lung cancer,adenocarcinoma occures most commonly and its incident rate is the highest.More and more studies evident that cell apoptosis inhibition is the major cause of tumorigenesis and progresss.Therefore,induction of apoptosis by drugs in lung adenocarcinoma cells is an indispensable strategy for lung adenocarcinoma therapy,which would decrease lung cancer mortality.In this article,we aimed to screen small molecules to effectively promote lung adenocarcinoma A549 cell apoptosis by using Chemical Genetics,the novel technology platform.Besides,we also aimed to investigate the mechanisms by which the small compounds function.This study would lay the foundation for us to insight into the proteins targeted by the small molecules,and would provide a theoretical basis for developing anti-lung adenocarcinoma agents.
STUDY CONTENTS:
1 Screening the small molecules initially.
2 Identification of apoptosis induction in A549 cells by small molecules.
3 Study the mechanisms of the small molecules inducing apoptosis in A549 cells
METHODS:
1.MTT assay for cell viability,by which small molecules were screened initially.
2.The morphological changes were observed under phase contrast microscope.
3.LDH assay to determine whether the cells treated by the small molecules undergo necrosis.
4.DNA nuclear fragmentation was analyzed by acridine orange staining.
5.The TdT-mediated dUTP nick end labeling technique was used to detect in situ nuclear DNA fragmentation and count apoptosis ratio
6.The fluorescence probe,DCHF was used to analyze ROS level.
7.The change of the mitochondrial membrane potential was measured by the TMRM staining as described previously[Falchi et al,2005]
8.The expression of integrinβ4 was analysised by immunofluorescence assay.
RESULTS:
1.The effects of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives on A549 lung cancer cell growth
1.1 The results of MTT assay showed that 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives(1-5~#)could inhibit A549 lung cancer cell growth within 24-48 h,and in a time and dose dependent manner.
1.2 Cell morphological changes observed under Phase Contrast Microscope:When cells were exposed to 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives(1-5~#) 200μM for 24h,morphological changes were found,including cell shrinkage, round and cell viability decreased.
2.The effects of 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a] pyrazin-4(5H)-one derivatives on A549 lung cancer cell growth
2.1 The results of MTT assay showed that all kinds of six 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a] pyrazin-4(5H)-one derivatives(8a-8f)could decrease cell viability markedly within 24-48 h,and in a time and dose dependent manner.
2.2 Cell morphological changes observed under Phase Contrast Microscope:When cells were exposed to 8d-8f 20μM for 24-48h,morphological changes which exhibiting the classical characteristics of apoptosis occurred.
2.3 Nuclear fragmentation assay by AO staining in conjunction with laser scanning confocal microscopy(LSCM)showed that when incubation with 8d-8f 20μM for 48 h,many cells showed red-orange nuclear fragments and apoptotic bodies.
2.4 LDH assay showed that when the cells were incubated with 8d-8f 20μM for 48 h,there was no significant difference(p＞0.05)in LDH release between the control group and the test group.
2.5 TUNEL assay showed that the 8d-8f 20μM and 48h treatment group showed an overwhelming majority of apoptotic A549 cells(P＜0.01).
2.6 When A549 cells were treated with 8d-8f 20μM for 48h,the intracellular ROS level was decreased obviously(P＜0.01).
2.7 When A549 cells were treated with 8d-8f 20μM for 48h,the mitochondrial membrane potential level was decreased obviously(P＜0.01).
2.8 The results ofβ4 protein expression detected by immuno-fluorescence assay combined with LSCM showed that when A549 cells were treated with 8d-8f 20μM for 48h,the relative level ofβ4 was up-regulated markedly(p＜0.01).
CONCLUSION:
1.Based on the initial screen of the small molecules,we concluded that all of the five kinds of small molecules could inhibit the proliferation of A549 human lung cancer cells,but their abilities in proliferation inhibition were quite different.2~#、3~# and 5~# were the most powerful.
2.The results of MTT assay showed that all kinds of six 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a] pyrazin-4(5H)-one derivatives(8a-8f)could decrease cell viability markedly,but their abilities in proliferation inhibition were quite different.8d、8e and 8f were the most powerful,so our research was mainly focused on the effects of 8d-8f on the proliferation of A549 cells and the mechanisms by which the small compound functioned.
3.8d、8e and 8f,20μM,could induce apoptosis in A549 human lung cancer cells. They might perform their functions by up-regulation of ROS level and effect the mitochondrial membrane potential level.
4.Integrinβ4 level was up-regulation also,suggesting that integrinβ4 might be a key factor in the signal apoptosis.
研究目的
近年来,肺癌死亡率居于各种恶性肿瘤之首位,其中肺腺癌最常见并且其发病率最高。由于肿瘤发生和生长的主要原因在于细胞凋亡受到抑制,因此,诱导肺腺癌细胞凋亡是治疗肺腺癌的重要措施,也是降低肺癌死亡率的有力手段之一。本文以人肺腺癌A549细胞系为例,利用化学遗传学这一新兴技术平台,筛选有效的诱导肺腺癌细胞凋亡的小分子化合物并研究其凋亡诱导分子机制,为进一步研究小分子凋亡诱导剂的特异性靶蛋白这一后续工作奠定基础,同时为开发新型的肺腺癌治疗药物提供理论依据。
研究内容
1.对小分子化合物进行初步筛选
2.鉴定小分子化合物对A549细胞的凋亡诱导作用
3.研究小分子化合物诱导A549细胞凋亡的分子机制
研究方法
1.MTT法检测细胞存活率,由此对小分子化合物进行初步筛选
2.倒置相差显微镜观察细胞形态变化
3.LDH(乳酸脱氢酶)检测细胞是否出现坏死
4.吖啶橙染色结合激光扫描共聚焦显微镜观察,检测细胞核凝集
5.TUNEL染色检测DNA片段化和凋亡率
6.荧光探针DCHF检测ROS表达水平
7.利用TMRM染色检测细胞线粒体膜电位变化[Falchi et al,2005]
8.免疫荧光化学法检测膜整连蛋白β4的表达
研究结果
1苯并噁嗪酮衍生物对A549细胞的生长抑制作用
1.1 MTT检测结果表明,在24h-48h内,5种苯并嗯嗪酮衍生物(1-5~#)均能抑制A549细胞的生长,且其抑制作用呈现时间和浓度依赖性。
1.2倒置相差显微镜观察细胞形态发现:200μM苯并嗯嗪酮衍生物(1-5~#)分别处理A549细胞24h,细胞明显缩小,有的细胞变圆。
2二茂铁基吡唑并哌嗪化合物对A549细胞的凋亡诱导作用
2.1 MTT检测结果表明,在24h-48h内,6种二茂铁基吡唑并哌嗪化合物(8a-8f)均能显著降低A549细胞的存活率并且其作用效果呈现时间和浓度依赖性。
2.2倒置相差显微镜观察细胞形态发现:8d-8f各20μM分别处理A549细胞24h-48h,细胞呈现典型的凋亡形态学特征。
2.3吖啶橙染色结合激光扫描共聚焦显微镜检测细胞核片段化,发现:20μM8d-8f分别处理A549细胞48h时,细胞核固缩、染色质凝集、凋亡小体清晰可见。
2.4 LDH检测发现:8d-8f各20μM分别处理A549细胞48h时,与对照组细胞相比,培养液中LDH酶活浓度未发生显著性变化(P＞0.05)。
2.5 TUNEL染色发现,8d-8f各20μM分别处理A549细胞48h,TUNEL染色阳性率显著升高(P＜0.01)。
2.6使用荧光探针DCHF检测细胞内ROS水平的变化,结果发现,8d-8f各20μM分别处理A549细胞48h时,细胞内的ROS水平显著升高(P＜0.01)。
2.7利用TMRM染色检测细胞线粒体膜电位的变化,结果显示,8d-8f各20μM分别处理A549细胞48h时,细胞内的线粒体膜电位显著升高(P＜0.01)。
2.8免疫细胞化学检测发现,8d-8f各20μM分别处理A549细胞48h时,膜整连蛋白β4的水平显著升高(P＜0.01)。
结论
1.小分子化合物初步筛选结果表明,5种苯并噁嗪酮衍生物对A549细胞生长均有抑制作用,其中2~#、3~#和5~#化合物的抑制作用比较明显。
2.MTT初步筛选结果显示,6种二茂铁基吡唑并哌嗪化合物(8a-8f)对A549细胞增殖均有抑制作用,但其增殖抑制能力不同,其中8d、8e、8f三种小分子化合物增殖抑制能力较强,因此选取该三种小分子继续研究其对A549细胞的作用及其分子机制。
3.8d、8e、8f三种小分子化合物20μM均能诱导A549细胞凋亡,而该凋亡诱导作用可能是通过提高ROS水平和影响线粒体膜电位来实现的。
4.在8d、8e、8f三种小分子化合物诱导A549细胞凋亡的过程中,膜整连蛋白β4的表达水平升高,说明膜整连蛋白β4可能是该类小分子化合物诱导A549细胞凋亡途径中的一个重要因子。
INVESTIGATION OF SMALL MOLECULE-INDUCED APOPTOSIS AND THE MOLECULAR MECHANISMS IN A549 HUMAN LUNG CANCER CELLS
In recent years,lung cancer is the leading category of cancer threatening the health of the people in many countries,lung cancer mortality stands the first within all kinds of cancer death.Moreover,among all types of lung cancer,adenocarcinoma occures most commonly and its incident rate is the highest.More and more studies evident that cell apoptosis inhibition is the major cause of tumorigenesis and progresss.Therefore,induction of apoptosis by drugs in lung adenocarcinoma cells is an indispensable strategy for lung adenocarcinoma therapy,which would decrease lung cancer mortality.In this article,we aimed to screen small molecules to effectively promote lung adenocarcinoma A549 cell apoptosis by using Chemical Genetics,the novel technology platform.Besides,we also aimed to investigate the mechanisms by which the small compounds function.This study would lay the foundation for us to insight into the proteins targeted by the small molecules,and would provide a theoretical basis for developing anti-lung adenocarcinoma agents.
STUDY CONTENTS:
1 Screening the small molecules initially.
2 Identification of apoptosis induction in A549 cells by small molecules.
3 Study the mechanisms of the small molecules inducing apoptosis in A549 cells
METHODS:
1.MTT assay for cell viability,by which small molecules were screened initially.
2.The morphological changes were observed under phase contrast microscope.
3.LDH assay to determine whether the cells treated by the small molecules undergo necrosis.
4.DNA nuclear fragmentation was analyzed by acridine orange staining.
5.The TdT-mediated dUTP nick end labeling technique was used to detect in situ nuclear DNA fragmentation and count apoptosis ratio
6.The fluorescence probe,DCHF was used to analyze ROS level.
7.The change of the mitochondrial membrane potential was measured by the TMRM staining as described previously[Falchi et al,2005]
8.The expression of integrinβ4 was analysised by immunofluorescence assay.
RESULTS:
1.The effects of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives on A549 lung cancer cell growth
1.1 The results of MTT assay showed that 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives(1-5~#)could inhibit A549 lung cancer cell growth within 24-48 h,and in a time and dose dependent manner.
1.2 Cell morphological changes observed under Phase Contrast Microscope:When cells were exposed to 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives(1-5~#) 200μM for 24h,morphological changes were found,including cell shrinkage, round and cell viability decreased.
2.The effects of 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a] pyrazin-4(5H)-one derivatives on A549 lung cancer cell growth
2.1 The results of MTT assay showed that all kinds of six 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a] pyrazin-4(5H)-one derivatives(8a-8f)could decrease cell viability markedly within 24-48 h,and in a time and dose dependent manner.
2.2 Cell morphological changes observed under Phase Contrast Microscope:When cells were exposed to 8d-8f 20μM for 24-48h,morphological changes which exhibiting the classical characteristics of apoptosis occurred.
2.3 Nuclear fragmentation assay by AO staining in conjunction with laser scanning confocal microscopy(LSCM)showed that when incubation with 8d-8f 20μM for 48 h,many cells showed red-orange nuclear fragments and apoptotic bodies.
2.4 LDH assay showed that when the cells were incubated with 8d-8f 20μM for 48 h,there was no significant difference(p＞0.05)in LDH release between the control group and the test group.
2.5 TUNEL assay showed that the 8d-8f 20μM and 48h treatment group showed an overwhelming majority of apoptotic A549 cells(P＜0.01).
2.6 When A549 cells were treated with 8d-8f 20μM for 48h,the intracellular ROS level was decreased obviously(P＜0.01).
2.7 When A549 cells were treated with 8d-8f 20μM for 48h,the mitochondrial membrane potential level was decreased obviously(P＜0.01).
2.8 The results ofβ4 protein expression detected by immuno-fluorescence assay combined with LSCM showed that when A549 cells were treated with 8d-8f 20μM for 48h,the relative level ofβ4 was up-regulated markedly(p＜0.01).
CONCLUSION:
1.Based on the initial screen of the small molecules,we concluded that all of the five kinds of small molecules could inhibit the proliferation of A549 human lung cancer cells,but their abilities in proliferation inhibition were quite different.2~#、3~# and 5~# were the most powerful.
2.The results of MTT assay showed that all kinds of six 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a] pyrazin-4(5H)-one derivatives(8a-8f)could decrease cell viability markedly,but their abilities in proliferation inhibition were quite different.8d、8e and 8f were the most powerful,so our research was mainly focused on the effects of 8d-8f on the proliferation of A549 cells and the mechanisms by which the small compound functioned.
3.8d、8e and 8f,20μM,could induce apoptosis in A549 human lung cancer cells. They might perform their functions by up-regulation of ROS level and effect the mitochondrial membrane potential level.
4.Integrinβ4 level was up-regulation also,suggesting that integrinβ4 might be a key factor in the signal apoptosis.
引文
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Du A, Zhao B, Miao J, et al. Safrole oxide induces apoptosis by up-regulating Fas and FasL instead of integrin beta4 in A549 human lung cancer cells. Bioorg Med Chem. 2006 Apr 1;14(7):2438-45
Falchi AM, Isola R, Diana A, et al. Characterization of depolarization and repolarization phases of mitochondrial membrane potential fluctuations induced by tetramethylrhodamine methyl ester photoactivation. FEBS J. 2005 Apr;272(7): 1649-59.
Feeney CJ, Pennefather PS, Gyulkhandanyan AV. A cuvette-based fluorometric analysis of mitochondrial membrane potential measured in cultured astrocyte monolayers. J Neurosci Methods. 2003 May 30;125(1-2): 13-25.
Feng C, Ye C, Liu X, et al. Beta4 integrin is involved in statin-induced endothelial cell death. Biochem Biophys Res Commun. 2004 Oct 22;323(3): 858-64.
Foster KA, Oster CG, Mayer MM, et al. Characterization of the A549 cell line as a type Ⅱ pulmonary epithelial cell model for drug metabolism. Exp Cell Res. 1998 Sep 15;243(2):359-66.
Freeman BA, Crapo JD. Biology of disease: free radicals and tissue injury. Lab Invest. 1982 Nov;47(5):412-26.
Gardiner L, Coyle BJ, Chan WC, et al. Discovery of antagonist peptides against bacterial helicase-primase interaction in B. stearothermophilus by reverse yeast three-hybrid. Chem Biol. 2005 May;12(5):595-604.
Goel A, Prasad AK, Parmar VS, et al. 7,8-Dihydroxy-4-methylcoumarin induces apoptosis of human lung adenocarcinoma cells by ROS-independent mitochondrial pathway through partial inhibition of ERK/MAPK signaling. FEBS Lett. 2007 May 29;581(13):2447-54.
Horswill AR, Benkovic SJ. Cyclic peptides, a chemical genetics tool for biologists. Cell Cycle. 2005 Apr; 4(4):552-5.
Huang Z. The Chemical Biology of Apoptosis. Exploring Protein-Protein Interactions and the Life and Death of Cells with Small Molecules. Chem Biol. 2002 Oct;9(10): 1059-72.
Jarvinen K, Pietarinen-Runtti P, Linnainmaa K, et al. Antioxidant defense mechanisms of human mesothelioma and lung adenocarcinoma cells. Am J Physiol Lung Cell Mol Physiol. 2000 Apr;278(4): L696-702.
Jones SP, Teshima Y, Akao M, et al. Simvastatin attenuates oxidant-induced mitochondrial dysfunction in cardiac myocytes. Circ Res. 2003 Oct 17;93(8):697-9.
Kajiji S, Tamura RN, Quaranta V. A novel integrin (alpha E beta 4) from human epithelial cells suggests a fourth family of integrin adhesion receptors. EMBO J. 1989 Mar;8(3):673-80.
Kang YH, Lee E, Choi MK, et al. Role of reactive oxygen species in the induction of apoptosis by alpha-tocopheryl succinate. Int J Cancer. 2004 Nov 10;112(3):385-92
Kato K, Shiga K, Yamaguchi K, et al. Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signaling. Biochem J. 2006 Mar 15;394(Pt 3):647-56
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4): 239-57.
Kim R, Emi M, Tanabe K. Caspase-dependent and -independent cell death pathways after DNA damage. Oncol Rep. 2005 Sep;14(3):595-9.
Kim YH, Shin HC, Song DW, et al. Arisostatins A induces apoptosis through the activation of caspase-3 and reactive oxygen species generation in AMC-HN-4 cells. Biochem Biophys Res Commun. 2003 Sep 19;309(2):449-56.
Koster J, van Wilpe S, Kuikman I, et al. Role of binding of plectin to the integrin beta4 subunit in the assembly of hemidesmosomes. Mol Biol Cell. 2004 Mar; 15(3): 1211-23.
Kroemer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis. Immunol Today. 1997 Jan; 18(1):44-51.
Kroemer G. Mitochondrial control of apoptosis: an introduction. Biochem Biophys Res Commun. 2003 May 9;304(3):433-5.
Kroemer G, Petit P, Zamzami N, et al. The biochemistry of programmed cell death. FASEB J. 1995 Oct;9(13): 1277-87
Kuo CT, Hsu MJ, Chen BC, et al. Denbinobin induces apoptosis in human lung adenocarcinoma cells via Akt inactivation, Bad activation, and mitochondrial dysfunction. Toxicol Lett. 2008 Feb 28;177(1):48-58
Lee ER, Kang YJ, Choi HY, et al. Induction of apoptotic cell death by synthetic naringenin derivatives in human lung epithelial carcinoma A549 cells. Biol Pharm Bull. 2007 Dec;30(12):2394-8.
Lee E, Choi MK, Youk HJ, et al. 5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3- trifluoromethylpyrazole acts in a reactive oxygen species-dependent manner to suppress human lung cancer growth. J Cancer Res Clin Oncol. 2006 Apr;132(4):223-33.
Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001 Jul 5;412(6842):95-9.
Lin HI, Lee YJ, Chen BF, et al. Involvement of Bcl-2 family, cytochrome c and caspase 3 in induction of apoptosis by beauvericin in human non-small cell lung cancer cells. Cancer Lett. 2005 Dec 18; 230(2): 248-59.
Lockshin, RA; Williams, CM. Programmed cell death. II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J Insect Physiol 1964 Dec 10: 643-9.
Lv X, Su L, Yin D, et al. Knockdown of integrin beta4 in primary cultured mouse neurons blocks survival and induces apoptosis by elevating NADPH oxidase activity and reactive oxygen species level. Int J Biochem Cell Biol. 2008;40(4):689-99.
Mainiero F, Murgia C, Wary KK, et al. The coupling of a6p4 integrin to the ras-MAPK pathways mediated by shc controls keratinocyte proliferation. EMBO J. 1997 May 1;16(9):2365-75.
Malet G, Martin AG, Orzaez M, et al. Small molecule inhibitors of Apaf-1 -related caspase- 3/-9 activation that control mitochondrial-dependent apoptosis. Cell Death Differ. 2006 Sep; 13(9): 1523-32.
Matsuyama S, Llopis J, Deveraux QL, et al. Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nat Cell Biol. 2000 Jun;2(6):318-25.
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Panduri V,Weitzman SA,Chandel NS,et al.Mitochondrial-derived free radicals mediate asbestos-induced alveolar epithelial cell apoptosis.Am J Physiol Lung Cell Mol Physiol.2004 Jun;286(6):L1220-7.
Poppe M,Reimertz C,Dussmann H,et al.Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis.J Neurosci.2001 Jul 1;21(13):4551-63
Preston TJ,Abadi A,Wilson L,et al.Mitochondrial contributions to cancer cell physiology:potential for drug development.Adv Drug Deliv Rev.2001 Jul 2;49(1-2):45-61
Ptasznik A,Nakata Y,Kalota A,et al.Short interfering RNA(siRNA)targeting the Lyn kinase induces apoptosis in primary,and drug-resistant,BCR-ABL 1(+)leukemia cells.Nat Med.2004 Nov;10(11):1187-9.
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Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol. 1999 Sep;17(9):2941-53.
Rivera MR Multimodality therapy in the treatment of lung cancer. Semin Respir Crit Care Med. 2004,25 Suppl 1:3-10.
Sakakura C, Hagiwara A, Nakanishi M, et al. Differential gene expression profiles of gastric cancer cells established from primary tumour and malignant ascites. Br J Cancer. 2002 Nov 4;87(10): 1153-61.
Schagger H. Respiratory chain supercomplexes. IUBMB Life. 2001 Sep-Nov;52(3-5): 119-28.
Schreiber SL. Chemical genetics resulting from a passion for synthetic organic chemistry. Bioorg Med Chem. 1998 Aug;6(8): 1127-52.
Shibata Y, Branicky R, Landaverde IO, et al. Redox regulation of germline and vulval development in caenorhabditis elegans. Science. 2003 Dec 5;302(5651): 1779-82.
Simamura E, Hirai K, Shimada H, et al. Mitochondrial damage prior to apoptosis in furanonaphthoquinone treated lung cancer cells. Cancer Detect Prev. 2003;27(1):5-13.
Simon HU, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 2000 Nov;5(5):415-8.
Spring DR. Chemical genetics to chemical genomics: small molecules offer big insights. Chem Soc Rev. 2005 Jun;34(6):472-82.
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Stefanis L. Caspase-dependent and -independent neuronal death: two distinct pathways to neuronal injury. Neuroscientist. 2005 Feb;11(1):50-62.
Stockwell BR. Chemical Genetics: Ligand-Based Discovery of Gene Function. Nature Reviews Genetics. 2000 Nov;1(2): 116-25.
Strausberg RL, Schreiber SL. From Knowing to Controlling: A Path from Genomics to Drugs Using Small Molecule Probes. Science. 2003 Apr 11;300(5617):294-5.
Su YT, Chang HL, Shyue SK, et al. Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway. Biochem Pharmacol. 2005 Jul 15 ;70(2): 229-41
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Cregan SP, Dawson VL, Slack RS. Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene. 2004 Apr 12;23(16):2785-96.
Dowling J, Yu QC, Fuchs E. β4 integrin is required for hemidesmosome formation,cell adhesion and cell survival. J Cell Biol. 1996 Jul;134(2):559-72.
Du A, Zhao B, Miao J, et al. Safrole oxide induces apoptosis by up-regulating Fas and FasL instead of integrin beta4 in A549 human lung cancer cells. Bioorg Med Chem. 2006 Apr 1;14(7):2438-45
Falchi AM, Isola R, Diana A, et al. Characterization of depolarization and repolarization phases of mitochondrial membrane potential fluctuations induced by tetramethylrhodamine methyl ester photoactivation. FEBS J. 2005 Apr;272(7): 1649-59.
Feeney CJ, Pennefather PS, Gyulkhandanyan AV. A cuvette-based fluorometric analysis of mitochondrial membrane potential measured in cultured astrocyte monolayers. J Neurosci Methods. 2003 May 30;125(1-2): 13-25.
Feng C, Ye C, Liu X, et al. Beta4 integrin is involved in statin-induced endothelial cell death. Biochem Biophys Res Commun. 2004 Oct 22;323(3): 858-64.
Foster KA, Oster CG, Mayer MM, et al. Characterization of the A549 cell line as a type Ⅱ pulmonary epithelial cell model for drug metabolism. Exp Cell Res. 1998 Sep 15;243(2):359-66.
Freeman BA, Crapo JD. Biology of disease: free radicals and tissue injury. Lab Invest. 1982 Nov;47(5):412-26.
Gardiner L, Coyle BJ, Chan WC, et al. Discovery of antagonist peptides against bacterial helicase-primase interaction in B. stearothermophilus by reverse yeast three-hybrid. Chem Biol. 2005 May;12(5):595-604.
Goel A, Prasad AK, Parmar VS, et al. 7,8-Dihydroxy-4-methylcoumarin induces apoptosis of human lung adenocarcinoma cells by ROS-independent mitochondrial pathway through partial inhibition of ERK/MAPK signaling. FEBS Lett. 2007 May 29;581(13):2447-54.
Horswill AR, Benkovic SJ. Cyclic peptides, a chemical genetics tool for biologists. Cell Cycle. 2005 Apr; 4(4):552-5.
Huang Z. The Chemical Biology of Apoptosis. Exploring Protein-Protein Interactions and the Life and Death of Cells with Small Molecules. Chem Biol. 2002 Oct;9(10): 1059-72.
Jarvinen K, Pietarinen-Runtti P, Linnainmaa K, et al. Antioxidant defense mechanisms of human mesothelioma and lung adenocarcinoma cells. Am J Physiol Lung Cell Mol Physiol. 2000 Apr;278(4): L696-702.
Jones SP, Teshima Y, Akao M, et al. Simvastatin attenuates oxidant-induced mitochondrial dysfunction in cardiac myocytes. Circ Res. 2003 Oct 17;93(8):697-9.
Kajiji S, Tamura RN, Quaranta V. A novel integrin (alpha E beta 4) from human epithelial cells suggests a fourth family of integrin adhesion receptors. EMBO J. 1989 Mar;8(3):673-80.
Kang YH, Lee E, Choi MK, et al. Role of reactive oxygen species in the induction of apoptosis by alpha-tocopheryl succinate. Int J Cancer. 2004 Nov 10;112(3):385-92
Kato K, Shiga K, Yamaguchi K, et al. Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signaling. Biochem J. 2006 Mar 15;394(Pt 3):647-56
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4): 239-57.
Kim R, Emi M, Tanabe K. Caspase-dependent and -independent cell death pathways after DNA damage. Oncol Rep. 2005 Sep;14(3):595-9.
Kim YH, Shin HC, Song DW, et al. Arisostatins A induces apoptosis through the activation of caspase-3 and reactive oxygen species generation in AMC-HN-4 cells. Biochem Biophys Res Commun. 2003 Sep 19;309(2):449-56.
Koster J, van Wilpe S, Kuikman I, et al. Role of binding of plectin to the integrin beta4 subunit in the assembly of hemidesmosomes. Mol Biol Cell. 2004 Mar; 15(3): 1211-23.
Kroemer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis. Immunol Today. 1997 Jan; 18(1):44-51.
Kroemer G. Mitochondrial control of apoptosis: an introduction. Biochem Biophys Res Commun. 2003 May 9;304(3):433-5.
Kroemer G, Petit P, Zamzami N, et al. The biochemistry of programmed cell death. FASEB J. 1995 Oct;9(13): 1277-87
Kuo CT, Hsu MJ, Chen BC, et al. Denbinobin induces apoptosis in human lung adenocarcinoma cells via Akt inactivation, Bad activation, and mitochondrial dysfunction. Toxicol Lett. 2008 Feb 28;177(1):48-58
Lee ER, Kang YJ, Choi HY, et al. Induction of apoptotic cell death by synthetic naringenin derivatives in human lung epithelial carcinoma A549 cells. Biol Pharm Bull. 2007 Dec;30(12):2394-8.
Lee E, Choi MK, Youk HJ, et al. 5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3- trifluoromethylpyrazole acts in a reactive oxygen species-dependent manner to suppress human lung cancer growth. J Cancer Res Clin Oncol. 2006 Apr;132(4):223-33.
Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001 Jul 5;412(6842):95-9.
Lin HI, Lee YJ, Chen BF, et al. Involvement of Bcl-2 family, cytochrome c and caspase 3 in induction of apoptosis by beauvericin in human non-small cell lung cancer cells. Cancer Lett. 2005 Dec 18; 230(2): 248-59.
Lockshin, RA; Williams, CM. Programmed cell death. II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J Insect Physiol 1964 Dec 10: 643-9.
Lv X, Su L, Yin D, et al. Knockdown of integrin beta4 in primary cultured mouse neurons blocks survival and induces apoptosis by elevating NADPH oxidase activity and reactive oxygen species level. Int J Biochem Cell Biol. 2008;40(4):689-99.
Mainiero F, Murgia C, Wary KK, et al. The coupling of a6p4 integrin to the ras-MAPK pathways mediated by shc controls keratinocyte proliferation. EMBO J. 1997 May 1;16(9):2365-75.
Malet G, Martin AG, Orzaez M, et al. Small molecule inhibitors of Apaf-1 -related caspase- 3/-9 activation that control mitochondrial-dependent apoptosis. Cell Death Differ. 2006 Sep; 13(9): 1523-32.
Matsuyama S, Llopis J, Deveraux QL, et al. Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nat Cell Biol. 2000 Jun;2(6):318-25.
MG Nievers, RQ Schaapveld, LC Oomen, et al. Ligand-independent role of the beta 4 integrin subunit in the formation of hemidesmosomes. J Cell Sci. 1998 Jun;111 (Pt 12):1659-72.
Miao JY,Araki S,Zhang SL,et al.1-Methyl-з-isobutylxanthine delays apoptosis induced by deprivation of growth factors in vascular endothelial cells.Acta Pharmacol Sin.2000 Oct;21(10):936-8.
Morena A,Riccioni S,Marchetti A,et al.Expression of the beta 4 integrin subunit induces monocytic differentiation of 32D/v-Abl cells.Blood.2002 Jul 1;100(1):96-106.
Nikolopoulos SN,Blaikie P,Yoshioka T,et al.Integrin beta4 signaling promotes tumor angiogenesis.Cancer Cell.2004 Nov;6(5):471-83.
Nikolopoulos SN,Blaikie P,Yoshioka T,et al.Targeted deletion of the integrin beta4signaling domain suppresses laminin-5-dependent nuclear entry of mitogen-activated protein kinases and NF-kappaB,causing defects in epidermal growth and migration.Mol Cell Biol.2005 Jul;25(14):6090-6102.
Oberhammer F,Fritsch G,Schmied M,et al.Condensation of the chromatin at the membrane of an apoptotic nucleus is not associated with activation of an endonuclease.J Cell Sci.1993 Feb;104(Pt 2):317-26.
Panduri V,Weitzman SA,Chandel NS,et al.Mitochondrial-derived free radicals mediate asbestos-induced alveolar epithelial cell apoptosis.Am J Physiol Lung Cell Mol Physiol.2004 Jun;286(6):L1220-7.
Poppe M,Reimertz C,Dussmann H,et al.Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis.J Neurosci.2001 Jul 1;21(13):4551-63
Preston TJ,Abadi A,Wilson L,et al.Mitochondrial contributions to cancer cell physiology:potential for drug development.Adv Drug Deliv Rev.2001 Jul 2;49(1-2):45-61
Ptasznik A,Nakata Y,Kalota A,et al.Short interfering RNA(siRNA)targeting the Lyn kinase induces apoptosis in primary,and drug-resistant,BCR-ABL 1(+)leukemia cells.Nat Med.2004 Nov;10(11):1187-9.
Raymond K,Kreft M,Janssen H,et al.Keratinocytes display normal proliferation,survival and differentiation in conditional {beta}4-integrin knockout mice.J Cell Sci. 2005 Mar 1;118(Pt 5):1045-60.
Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol. 1999 Sep;17(9):2941-53.
Rivera MR Multimodality therapy in the treatment of lung cancer. Semin Respir Crit Care Med. 2004,25 Suppl 1:3-10.
Sakakura C, Hagiwara A, Nakanishi M, et al. Differential gene expression profiles of gastric cancer cells established from primary tumour and malignant ascites. Br J Cancer. 2002 Nov 4;87(10): 1153-61.
Schagger H. Respiratory chain supercomplexes. IUBMB Life. 2001 Sep-Nov;52(3-5): 119-28.
Schreiber SL. Chemical genetics resulting from a passion for synthetic organic chemistry. Bioorg Med Chem. 1998 Aug;6(8): 1127-52.
Shibata Y, Branicky R, Landaverde IO, et al. Redox regulation of germline and vulval development in caenorhabditis elegans. Science. 2003 Dec 5;302(5651): 1779-82.
Simamura E, Hirai K, Shimada H, et al. Mitochondrial damage prior to apoptosis in furanonaphthoquinone treated lung cancer cells. Cancer Detect Prev. 2003;27(1):5-13.
Simon HU, Haj-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 2000 Nov;5(5):415-8.
Spring DR. Chemical genetics to chemical genomics: small molecules offer big insights. Chem Soc Rev. 2005 Jun;34(6):472-82.
Stagge V, Seufferlein T, Durschmied D, et al. Integrin-mediated differentiation of a pancreatic carcinoma cell line is independent of FAK or MAPK activation levels.Pancreas. 2001 Oct;23(3):236-45.
Stefanis L. Caspase-dependent and -independent neuronal death: two distinct pathways to neuronal injury. Neuroscientist. 2005 Feb;11(1):50-62.
Stockwell BR. Chemical Genetics: Ligand-Based Discovery of Gene Function. Nature Reviews Genetics. 2000 Nov;1(2): 116-25.
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