OXIDANTS AND CELL DEATH
氧化剂和细胞死亡
基本信息
- 批准号:6293782
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
The goal of our work is to elucidate the consequences of
exposure of biological substrates to oxidative stress. In
these studies, we investigate how oxidants may affect tumor
progression, focusing on the two following questions: (1) how
are tumor cells killed by oxidative stress? and (2) how can
oxidants modulate tumor cell killing by anti-neoplastic drugs?
Inherent in these studies is an investigation of cell death
pathways. Cell death can occur through several different
mechanisms which are distinguished by unique morphological and
biochemical traits. The two most widely described forms of
cell death are necrosis and apoptosis. Cells dying by
apoptosis fragment into subcellular "apoptotic bodies" while
cells dying by necrosis swell and then lyse. It is thought
that death by apoptosis is physiologically advantageous
because apoptotic cells can be phagocytosed by nearby cells
such that the contents are degraded intracellularly. In
contrast, death by necrosis is thought to promote an
inflammatory response caused by the release of the
intracellular contents. Most chemotherapeutic agents kill
tumor cells by inducing apoptosis.
Oxidants such as superoxide, hydrogen peroxide (H2O2), and
the hydroxyl radical are generated under a variety of
conditions in vivo such as during acute and chronic
inflammation. Solid tumors are often infiltrated by
inflammatory phagocytes which can generate oxidative stress
within the tumor tissue. Treatment of cells in vitro with
H2O2 causes DNA strand breaks, oxidation of lipids and
proteins, activation of poly(ADP)-ribosylation, and depletion
of cellular energy stores. We have found that in the presence
of H2O2, human B lymphoma cells are unable to undergo
apoptosis. This was established using the chemotherapy drug
VP-16 to induce apoptosis in Burkitt's lymphoma cell lines and
measuring markers of apoptotic death, including cell
morphology (fluorescence microscopy), annexin V binding (FACS
analysis), induction of an oligonucleosomal endonuclease
(agarose gel electrophoresis), and caspase activation (enzyme
assays and Western blot immunoassays). When cells are treated
with VP-16 in the presence of 75-100 ?M H2O2, all of these
biochemical hallmarks of apoptosis are inhibited and the cells
undergo non-apoptotic cell death, similar to the death
observed when they are treated with H2O2 alone. The mechanism
whereby H2O2 inhibits apoptosis is by depleting the cells of
ATP. The effects of H2O2 can be overcome by inhibitors of
poly(ADP)-ribosylation, which preserve cellular ATP levels,
and can be mimicked by agents such as oligomycin which inhibit
ATP synthesis. Overall, our data show that H2O2 can
manipulate cell death pathways, diverting the cell away from
apoptosis. The main physiological significance of these
findings will be found in whether oxidative stress interferes
with chemotherapy-induced tumor cell death and clearance in
vivo. Experiments are currently underway to address this
question.
我们工作的目标是阐明
生物基质暴露于氧化应激。 在
在这些研究中,我们研究了氧化剂如何影响肿瘤
进展,重点是以下两个问题:(1)如何
肿瘤细胞会被氧化应激杀死吗?(2)如何
氧化剂通过抗肿瘤药物调节肿瘤细胞的杀伤?
这些研究的本质是对细胞死亡的调查
路径。 细胞死亡可以通过几种不同的方式发生
独特的形态学特征和
生化特征 两种最广泛描述的形式
细胞死亡是坏死和凋亡。 细胞死亡
细胞凋亡片段成亚细胞“凋亡小体”,
因坏死而死亡的细胞膨胀然后溶解。 据认为
细胞凋亡导致的死亡在生理上是有利的
因为凋亡细胞可以被附近的细胞吞噬
使得内容物在细胞内降解。 在
相比之下,坏死性死亡被认为会促进
炎症反应引起的释放的
胞内内容物 大多数化疗药物杀死
通过诱导细胞凋亡。
氧化剂如超氧化物、过氧化氢(H2 O2)和
羟基自由基是在各种
体内条件,例如在急性和慢性
炎症 实体瘤通常被
炎性吞噬细胞可产生氧化应激
在肿瘤组织中。 用以下物质体外处理细胞:
H2 O2导致DNA链断裂,脂质氧化,
蛋白质、聚(ADP)-核糖基化的活化和消耗
细胞能量储存。 我们发现,
人B淋巴瘤细胞不能经受
凋亡 这是通过使用化疗药物
VP-16在伯基特淋巴瘤细胞系中诱导凋亡,
测量凋亡性死亡的标志物,包括细胞
形态学(荧光显微镜)、膜联蛋白V结合(FACS
分析),寡核小体核酸内切酶的诱导
(琼脂糖凝胶电泳)和半胱天冬酶活化(酶
测定和Western印迹免疫测定)。 处理细胞时所
在75-100人面前用VP-16 M H2 O2,所有这些
细胞凋亡的生化标志被抑制,
经历非凋亡性细胞死亡,类似于
当它们单独用H2 O2处理时观察到。 机制
H2 O2抑制细胞凋亡是通过消耗细胞中的
ATP H_2O_2的影响可以通过以下抑制剂来克服:
聚(ADP)-核糖基化,其保持细胞ATP水平,
并且可以被抑制剂如寡霉素模拟
ATP合成。 总的来说,我们的数据表明,H2 O2可以
操纵细胞死亡途径,将细胞从
凋亡 这些的主要生理意义
研究结果将发现氧化应激是否会干扰
化疗诱导的肿瘤细胞死亡和清除,
vivo. 目前正在进行实验以解决这一问题
问题
项目成果
期刊论文数量(0)
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会议论文数量(0)
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