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标题: [news]New compound discovered that rapidly kills liver cancer [打印本页]

作者: StephenW 时间: 2012-3-19 16:14 标题: [news]New compound discovered that rapidly kills liver cancer

                                 http://blog.vcu.edu/massey_news/2012/03/new-compound-discovered-that-rapidly-kills-liver-cancer.html
New compound discovered that rapidly kills liver cancer                                                                         March 13, 2012 10:16 AM                                                                               | No Comments

Scientists have identified a new compound that rapidly kills hepatocellular carcinoma (HCC) cells, the most common form of liver cancer and fifth most common cancer worldwide, while sparing healthy tissue. The compound, Factor Qunolinone Inhibitor 1 (FQI1), works by inhibiting an oncogene originally discovered by a team of researchers led by Devanand Sarkar, M.B.B.S., Ph.D., Harrison Scholar at Virginia Commonwealth University (VCU) Massey Cancer Center, Blick Scholar and assistant professor in the Department of Human and Molecular Genetics and member of the VCU Institute of Molecular Medicine at VCU School of Medicine.

Recently published in the journal Proceedings of the National Academy of Sciences, the study demonstrates that HCC cells have what is known as an "oncogene addiction" to the transcription factor Late SV40 Factor (LSF). Oncogene addiction is a term used when a cancer cell is found to be dependent on a single gene to survive. Using the compound Factor Qunolinone Inhibitor 1 (FQI1), the scientists prevented LSF from binding to HCC DNA during the transcription process, which is the first step in a series of actions that lead to cell division and duplication. This action caused rapid HCC cell death in laboratory experiments and a dramatic reduction in tumor growth in mouse models with no observable toxicity to normal liver cells.

"We may be on the verge of developing a new, effective drug for liver cancer," says Sarkar. "In the last 2-3 years, my laboratory demonstrated the role of LSF in liver cancer and my collaborators at Boston University screened over 110,000 compounds to identify the ones that inhibit LSF function. FQI1 was identified as one of a class of effective compounds, but we never anticipated it would work this well."

Sarkar discovered LSF's role in liver cancer in 2010 when he demonstrated significantly higher LSF levels in HCC patients in comparison to healthy individuals, and showed that inhibition of LSF reduced the progression of HCC in laboratory experiments. This finding led to the collaboration between VCU and Boston University that resulted in the discovery of FQI1.

Now that FQI1 has been identified, pharmacokinetic studies are being conducted to determine how the drug behaves in the human body. Once the scientists have determined how the drug is absorbed, distributed, metabolized and eliminated from the body, they will work with clinicians to translate their findings into phase I clinical trials in patients with liver cancer.

"We have proven this compound is effective and nontoxic in living animals," says Sarkar. "While we won't know how FQI1 reacts in humans until the first clinical trial, we are very excited by our findings and hope they lead to a new drug for a disease that is currently very difficult to treat."

The lead investigators on this study were Trevor J. Grant and Joshua Bishop, Ph.D., from Boston University. In addition to Grant and Bishop, Sarkar collaborated with Ayesha Siddiq, Ph.D., Rachel Gredler and Xue-Ning Shen, M.D., from VCU School of Medicine; Jennifer Sherman and Kevin Fitzgerald, Ph.D., from Alnylam Pharmaceuticals, Inc.; Sriharsa Pradhan, Ph.D., from New England Biolabs, Inc.; Laura A. Briggs, Ph.D., and William H. Andrews, Ph.D., from Sierra Sciences, LLC; and Lisa Christadore, Girish Barot, Ph.D., Hang Gyeong Chin, Sarah Woodson, John Kavouris, Tracy Meehan, Scott E. Schaus, Ph.D., and Ulla Hansen, Ph.D., from Boston University.

The full manuscript is available online at: http://www.pnas.org/content/early/2012/03/02/1121601109.full.pdf+html

作者: StephenW 时间: 2012-3-19 16:14

新化合物发现，迅速杀死肝癌
2012年3月13日10:16 |没有评论
的SARKAR_D_160x240_092211.jpgScientists已经发现了一种新的化合物，迅速杀死肝细胞癌（HCC）细胞，肝癌最常见的形式和第五届全球最常见的癌症，同时保留健康组织。该化合物，的因素Qunolinone抑制剂1（FQI1），通过抑制癌基因最初是由一个研究团队由萨卡Devanand，内外全科医学士，博士，哈里森在弗吉尼亚联邦大学（VCU），梅西癌症中心，布利克学者的学术领导发现工作在人力和分子遗传学和分子医学VCU在VCU医学院研究所的成员系助理教授。

最近发表在国家科学院的期刊论文，研究表明，肝癌细胞有什么被称为“癌基因瘾”的转录因子，晚病毒因子（卤）。癌基因成瘾是癌细胞被发现是依赖于一个单一的基因生存时使用的一个术语。使用复合因子抑制剂Qunolinone 1（FQI1），科学家阻止LSF的结合，在肝癌基因的转录过程，这是在一系列的行动，导致细胞分裂和复制的第一步。这一行动引起快速肝癌细胞在实验室的实验死亡，在小鼠模型中肿瘤的生长，没有观察到的正常肝细胞的毒性急剧减少。

“我们可能是在开发一个新的有效的药物，肝癌的边缘，”萨卡说。 “我的实验室在过去的2-3年，表现出对LSF在肝癌中的作用，我在波士顿大学的合作者超过110,000种化合物筛选，以确定抑制LSF的功能。FQI1被确定为一类有效的化合物之一，但我们从来没有预料到它会工作，这口井。“

萨卡发现该组织于2010年在肝癌中的作用时，他表现出LSF的显着较高水平，在健康人相比，肝癌患者，并表明，抑制对LSF降低肝癌的实验室实验进展。这一发现导致弗吉尼亚联邦和美国波士顿大学之间的合作，导致发现FQI1的。

现在已经确定FQI1，药代动力学研究正在进行，以确定药物在人体中的行为如何。一旦科学家们已经确定的药物被吸收，分布，代谢和排出体外，他们将工作与临床医生，翻译成相我在肝癌患者的临床试验的结果。

“我们已经证明，这种化合物是有效的和无毒的活的动物，”萨卡说。他说：“虽然我们不知道如何FQI1在人类临床试验，直到第一个反应，我们非常高兴通过我们的调查结果，并希望他们导致的一种疾病，是目前非常难以治疗的新药物。”

特雷弗·J.格兰特和约书亚主教，博士，波士顿大学的这项研究的首席调查员。除了格兰特和主教，萨卡与西迪克麦嘉轩，博士，雷切尔Gredler和薛宁沉从弗吉尼亚联邦大学医学院，医学博士，珍妮弗谢尔曼和凯文·菲茨杰拉德，博士，从Alnylam制药公司师里哈萨普拉丹博士，从公司New England Biolabs公司;劳拉答：布里格斯，博士和威廉·H·安德鲁斯博士，从塞拉利昂科学，有限责任公司;和莉萨Christadore，吉里什巴罗特，博士，恒庆展，萨拉·伍德森，约翰Kavouris，特雷西·米汉，斯科特E. Schaus，博士，乌拉·汉森，博士，波士顿大学。

完整的手稿是在网上：http://www.pnas.org/content/earl ... 01109.full.pdf+html

作者: StephenW 时间: 2012-3-19 16:16

本帖最后由 StephenW 于 2012-3-19 16:18 编辑

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

- Author Affiliations

Departments of aBiology and
bChemistry, Center for Chemical Methodology and Library Development at Boston University, and
cProgram in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston MA 02215;
dNew England BioLabs, Inc., Ipswich, MA 01938;
eDepartment of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298;
fAlnylam Pharmaceuticals, Inc., Cambridge, MA 02142; and
gSierra Sciences, LLC, Reno, NV 89502

Edited by Jonathan R. Hart, The Scripps Research Institute, La Jolla, CA, and accepted by the Editorial Board January 31, 2012 (received for review January 3, 2012)

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Despite the prevalence of HCC, there is no effective, systemic treatment. The transcription factor LSF is a promising protein target for chemotherapy; it is highly expressed in HCC patient samples and cell lines, and promotes oncogenesis in rodent xenograft models of HCC. Here, we identify small molecules that effectively inhibit LSF cellular activity. The lead compound, factor quinolinone inhibitor 1 (FQI1), inhibits LSF DNA-binding activity both in vitro, as determined by electrophoretic mobility shift assays, and in cells, as determined by ChIP. Consistent with such inhibition, FQI1 eliminates transcriptional stimulation of LSF-dependent reporter constructs. FQI1 also exhibits antiproliferative activity in multiple cell lines. In LSF-overexpressing cells, including HCC cells, cell death is rapidly induced; however, primary or immortalized hepatocytes are unaffected by treatment with FQI1. The highly concordant structure–activity relationship of a panel of 23 quinolinones strongly suggests that the growth inhibitory activity is due to a single biological target or family. Coupled with the striking agreement between the concentrations required for antiproliferative activity (GI50s) and for inhibition of LSF transactivation (IC50s), we conclude that LSF is the specific biological target of FQIs. Based on these in vitro results, we tested the efficacy of FQI1 in inhibiting HCC tumor growth in a mouse xenograft model. As a single agent, tumor growth was dramatically inhibited with no observable general tissue cytotoxicity. These findings support the further development of LSF inhibitors for cancer chemotherapy.

作者: StephenW 时间: 2012-3-19 16:17

细胞增殖的小分子抑制剂的转录因子卤揭示该组织在肝癌基因成瘾

特雷弗·J.格兰塔，1，
约书亚答Bishopb，1,2，
丽莎研究Christadoreb，
吉里什Barota
恒庆CHINC，D，
萨拉Woodsona
约翰Kavourisb
麦嘉轩Siddiqe
雷切尔Gredlere
薛宁Shene，
詹妮弗Shermana，F，
特雷西Meehana
凯文Fitzgeraldf
师里哈萨Pradhand
劳拉答Briggsg，
威廉H. Andrewsg，
devanand Sarkare
的Scott E. Schausb，
3，C，乌拉Hansena

- 作者背景

部门的aBiology和
bChemistry，中心化学方法，并在波士顿大学图书馆的发展，
cProgram在分子生物学，细胞生物学，生物化学，波士顿大学，马萨诸塞州波士顿02215;
dNew England Biolabs公司，股份有限公司，伊普斯维奇，马01938;
eDepartment的人力和分子遗传学，弗吉尼亚联邦大学医学院，里士满，弗吉尼亚州23298;
fAlnylam制药公司，剑桥，麻省02142;
gSierra科学，有限责任公司，里诺，内华达州89502

由乔纳森·哈特，斯克里普斯研究所，拉霍亚加州，编辑和编委会2012年1月31日，审查，到2012年1月3日收到接受

抽象

肝细胞癌（HCC）是第五个世界最常见的癌症。尽管肝癌的患病率，有没有有效的全身治疗。转录因子LSF的是对化疗有前途的蛋白质目标是肝癌病人样本和细胞株中高表达，促进肝癌的啮齿类动物异种移植模型癌变。在这里，我们确定，有效地抑制LSF的细胞活性的小分子。喹啉酮抑制剂因子1（FQI1），抑制铅化合物，无论是在体外，电泳迁移率分析确定，LSF的DNA结合活性细胞中，藉由ChIP确定。与这种抑制一致，FQI1消除LSF的依赖记者结构的转录刺激。 FQI1还表现在多个细胞系的增殖活性。在LSF的过表达的细胞，包括肝癌细胞，迅速引起细胞死亡，但小学或永生化肝细胞不受治疗与FQI1的影响。 23喹哪啶小组高度一致的结构 - 活性关系，有力地表明，生长抑制活性，是由于一个单一的生物目标或家庭。再加上引人注目的协议之间的增殖活性（GI50s）和抑制LSF的转录（的IC50）所需的浓度，我们得出结论，该组织是生物FQIs具体目标。这些结果在体外的基础上，我们测试了在小鼠异种移植模型的肿瘤生长抑制肝癌的疗效FQI1。作为一个单一的代理，显着抑制肿瘤的生长，没有观察到的一般组织细胞毒性。这些发现支持了卤抑制剂用于癌症化疗的进一步发展。

作者: 9病成医 时间: 2012-3-19 21:18

是个好消息.

作者: 咬牙硬挺 时间: 2012-3-19 21:35

好消息感谢楼主，另外这两天论坛非常难上是怎么回事？

作者: 9病成医 时间: 2012-3-19 23:31

咬牙硬挺发表于 2012-3-19 21:35
好消息感谢楼主，另外这两天论坛非常难上是怎么回事？

难道也是重庆事件的影响?

作者: syyuwenhai 时间: 2012-3-20 13:35

顶，太好了，快点研究出来，救我爸呀。我们国家的政府咋就不能好好重视一下新药的研制呢。领导们睁开眼看看吧

作者: 把握当下 时间: 2012-3-21 08:48

very cool

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