已入深夜,您辛苦了!由于当前在线用户较少,发布求助请尽量完整的填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!祝你早点完成任务,早点休息,好梦!

Antileukemic Effects of the Novel Agent Elesclomol.

碘化丙啶 氧化应激 癌症研究 化学 细胞凋亡 生物 药理学 程序性细胞死亡 生物化学
作者
Sue Chow,Masazumi Nagai,Suqin He,Ronald K. Blackman,James Barsoum,Vojislav Vukovic,David W. Hedley
出处
期刊:Blood [American Society of Hematology]
卷期号:114 (22): 2736-2736 被引量:3
标识
DOI:10.1182/blood.v114.22.2736.2736
摘要

Abstract Abstract 2736 Poster Board II-712 Elesclomol (N-malonyl-bis (N′-methyl-N′-thiobenzoyl hydrazide)) is an investigational first-in-class oxidative stress inducer that triggers apoptosis in cancer cells (Kirshner et al., Mol Cancer Ther 2008;7:2319–27). In the clinic, elesclomol is well tolerated in humans and showed activity in combination with paclitaxel in patients with refractory solid tumors (Berkenblit et al., Clin Cancer Res 2007;13:584–90). The aims of the current study are to examine the activity of elesclomol against a range of AML cell lines, including primary patient blast cultures, to investigate the mechanisms of drug action and the potential to combine elesclomol with other agents, and to identify candidate biomarkers for monitoring effects during treatment of leukemia patients with elesclomol. Here we describe the effects of elesclomol treatment in 4 AML cell lines selected based on their varying molecular attributes. Effects on cellular redox state and mitochondrial function were monitored using a flow cytometry incorporating the glutathione (GSH) probe monobromobimane, the reactive oxygen species (ROS) probe carboxy-dichlorofluorescin and the mitochondrial membrane potential stain DiIC(1)5. In addition, outer cell membrane integrity was determined by propidium iodide exclusion. Dual staining of fixed, permeabilized cells with phospho-specific antibodies to p38 and SAPK/JNK was used to determine if elesclomol treatment results in activation of the stress-activated MAP kinase pathways. Elesclomol showed potent anti-leukemic effects in vitro at concentrations as low as 10nM, which is well below the concentrations achieved in cancer patients, and greater toxicity was achieved with prolonged drug exposure. In OCI-AML2, a factor-independent, poorly differentiated AML cell line, toxicity was associated with loss of reduced GSH that coincided with a large increase in ROS generation and depolarization of the mitochondrial inner membrane, and later with loss of surface membrane integrity. A similar pattern was seen in OCI-M2, a p53-deficient erythroblastic leukemia cell line, except that during the early stages of drug effect these cells showed a large increase in reduced GSH, suggesting that initially they are able to compensate for drug-induced oxidative stress through enhanced cellular antioxidant production. In contrast, the factor-dependent line OCI-AML5, which appeared most sensitive to elesclomol, showed loss of outer membrane integrity without obvious prior oxidative stress while the Flt-3 ITD mutant line MV4-11 showed an initial loss of mitochondrial membrane potential without accompanying oxidative stress. Strikingly, we did not observe activation of the stress-responsive p38 or SAPK/JNK pathways in any of these 4 cell lines tested, suggesting that this is not a prominent response to elesclomol activity in AML and that additional mechanisms may be at work for the activity of elesclomol in these cells. Further investigations are ongoing and additional studies, including evaluation of elesclomol activity in primary leukemic cells from AML patients, will be presented. In summary, elesclomol is a potent novel compound that exerts anti-leukemic effects in tissue culture at drug concentrations that are well below those achieved in patients, suggesting that it might be active in leukemia patients. Disclosures: Chow: Synta Pharmaceuticals Inc.: Research Funding. Nagai:Synta Pharmaceuticals Inc.: Employment. He:Synta Pharmaceuticals Inc.: Employment. Blackman:Synta Pharmaceuticals Inc.: Employment, Equity Ownership. Barsoum:Synta Pharmaceuticals Inc.: Employment, Equity Ownership. Vukovic:Synta Pharmaceuticals Inc.: Employment, Equity Ownership. Hedley:Synta Pharmaceuticals Inc.: Research Funding.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
1秒前
qbz发布了新的文献求助10
3秒前
杳鸢给杳鸢的求助进行了留言
4秒前
顾矜应助肉丸采纳,获得10
4秒前
5秒前
可爱易文完成签到,获得积分10
6秒前
李健应助乐观的安梦采纳,获得10
7秒前
可爱易文发布了新的文献求助10
10秒前
橘橘橘子皮完成签到 ,获得积分10
10秒前
归玖完成签到 ,获得积分10
11秒前
852应助欢呼妙彤采纳,获得10
13秒前
JamesPei应助里里采纳,获得10
15秒前
Lucas应助archer01采纳,获得10
16秒前
wcy完成签到 ,获得积分10
17秒前
ma发布了新的文献求助10
18秒前
Aray完成签到,获得积分10
19秒前
茜茜完成签到 ,获得积分10
20秒前
22秒前
23秒前
24秒前
苹果小八完成签到 ,获得积分10
24秒前
24秒前
fly发布了新的文献求助10
28秒前
自然秋双完成签到,获得积分10
30秒前
30秒前
30秒前
31秒前
31秒前
耿舒婷完成签到,获得积分10
33秒前
tuanheqi应助梨卜橙采纳,获得30
33秒前
十七完成签到 ,获得积分10
34秒前
orange完成签到,获得积分10
34秒前
CipherSage应助fly采纳,获得10
35秒前
团子发布了新的文献求助10
36秒前
ma完成签到,获得积分20
36秒前
小滕发布了新的文献求助10
36秒前
archer01发布了新的文献求助10
37秒前
脑洞疼应助www采纳,获得30
38秒前
完美世界应助士成采纳,获得10
42秒前
高分求助中
The late Devonian Standard Conodont Zonation 2000
Nickel superalloy market size, share, growth, trends, and forecast 2023-2030 2000
The Lali Section: An Excellent Reference Section for Upper - Devonian in South China 1500
Smart but Scattered: The Revolutionary Executive Skills Approach to Helping Kids Reach Their Potential (第二版) 1000
Very-high-order BVD Schemes Using β-variable THINC Method 830
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 800
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 800
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3248577
求助须知:如何正确求助?哪些是违规求助? 2892044
关于积分的说明 8269571
捐赠科研通 2560135
什么是DOI,文献DOI怎么找? 1388854
科研通“疑难数据库(出版商)”最低求助积分说明 650918
邀请新用户注册赠送积分活动 627798