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[英文新闻]Common Anti-Inflammatory Coaxes Liver Cancer Cells to Commit Suici [复制链接]

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发表于 2011-5-18 03:18 |只看该作者 |倒序浏览 |打印
本帖最后由 风雨不动 于 2012-4-14 15:18 编辑

在文章中提到许多中国科学家 [StephenW]
<http://www.sciencedaily.com/releases/2011/05/110516121545.htm>

Common Anti-Inflammatory Coaxes Liver Cancer Cells to Commit Suicide

ScienceDaily (May 16, 2011) — The anti-inflammatory drug celecoxib, known
by the brand name Celebrex, triggers liver cancer cell death by reacting
with a protein in a way that makes those cells commit suicide, according to
a new study.

Researchers also found that the combination of celecoxib with each of two
chemotherapy drugs killed more liver cancer cells in culture, making those
combinations more effective than either drug on its own.

"Each chemotherapy drug alone will reduce the growth of cancer cells, but
when each single drug is combined with Celebrex, a greater growth
suppression effect was observed," said Jiayuh Lin, senior author of the
study and an associate professor of pediatrics at Ohio State University.
"For clinicians, this research suggests the possibility of a new
therapeutic strategy."

Celecoxib has this effect by acting on STAT3, a gene inside liver cancer
cells that, when activated, allows those cancer cells to resist the effects
of chemotherapy drugs. The researchers determined that the celecoxib
molecule binds to STAT3 on so-called "hot spots," effectively blocking its
ability to function.

Powerful computing techniques were employed before the researchers ever
considered celecoxib as a potential treatment for cancer. Celebrex is a
nonsteroidal anti-inflammatory drug, or NSAID, and a Cox-2 inhibitor,
meaning it helps control inflammation by inhibiting an enzyme known as
cyclooxygenase-2. It is most commonly prescribed to treat the pain of
arthritis.

Chenglong Li, an assistant professor of medicinal chemistry and
pharmacognosy at Ohio State, has developed computer simulations to identify
optimal drug fragment combinations that attach simultaneously to proteins
in ways that block the proteins' functions. By searching a database of
existing federally approved drugs, he found that celecoxib was structurally
similar to a template molecule that he had determined would most
effectively bind to STAT3 and inhibit its function.

"Normally, STAT3 is persistently activated in cancer cells. If you have a
good molecule that sticks to STAT3, it will prevent its activation," Li
said. And when STAT3 is inhibited, cellular survival pathways are blocked
that cause the cancer cell to chop itself up and die.

The research appears online and is scheduled for later print publication in
the journal Cancer Prevention Research.

The biological portion of the study further defined the role of a
pro-inflammatory protein in liver cancer's development. The protein, called
interleukin-6, or IL-6, is a cytokine, a chemical messenger that causes
inflammation, which can have both beneficial and damaging effects in the
body. Previous research by other scientists has shown that high levels of
IL-6 in the blood are associated with hepatocellular carcinoma, the most
common type of liver cancer.

Lin and colleagues determined that IL-6 initiates a chemical reaction
called phosphorylation of STAT3. That reaction activates STAT3 inside liver
cancer cells, where STAT3 in turn activates at least three other known
genes that allow the cells to resist the effects of chemotherapy.

The scientists treated five different types of hepatocellular carcinoma
cells with two different doses of celecoxib for two hours, and followed by
giving them IL-6 for 30 minutes. The pre-treatment with the lower dose of
celecoxib inhibited IL-6's ability to start the reaction that activates
STAT3. The higher dose blocked STAT3 altogether.

The researchers then treated a line of liver cancer cells with celecoxib in
combination with two chemotherapy drugs: doxorubicin, which is used to
treat breast, ovarian, gastric, thyroid and several other cancers, and
sorafenib, which is the only chemotherapy medication approved by the Food
and Drug Administration for liver cancer treatment. Its brand name is
Nexavar.

With both drugs, the addition of celecoxib treatment reduced the number of
viable liver cancer cells by anywhere from approximately 50 percent to more
than 90 percent, depending on the doses. The combination of celecoxib and
sorafenib also significantly limited the cancer cells' ability to form
colonies, a key element of tumor growth and survival after the drug
treatment.

"Because liver cancer has a very low five-year survival rate, it is most
likely that even sorafenib alone may not be effective to cure the cancer,"
said Lin, also an investigator in Ohio State's Comprehensive Cancer Center
and the Center for Childhood Cancer at Nationwide Children's Hospital. "We
hope that using both drugs together could be more effective. Both celecoxib
and sorafenib are already approved by the FDA, so we think this combined
treatment should be able to be used in the clinic pretty quickly."

The fifth most common cancer in humans, liver cancer remains one of the
most difficult to successfully treat. Patients' overall five-year survival
rate is about 10 percent, according to the American Cancer Society.

These experiments were conducted in cell cultures. Further testing would be
needed to determine celecoxib's effectiveness in human cancers, Lin noted.

And the powerful computational work led by Li, also an investigator in Ohio
State's Comprehensive Cancer Center, is likely to lead to the development
of new molecules with even more precise structural relationships with the
proteins they are designed to block.

Li's method is called Multiple Ligand Simultaneous Docking. In this work,
he used computer simulations to identify "hot spots" on the STAT3 protein
-- tiny pockets to which molecules could most successfully attach to
inhibit the protein's activity. He then searched through drug banks
containing more than 7,500 existing and experimental medications to find
the most suitable molecular fragments that could be pieced together to
produce a new molecule shaped in such a way that it would fit into those
pockets.

After designing a template molecule that would most effectively bind to
STAT3, he compared that template to the 1,400 federally approved drugs
already on the market.

"Celecoxib is almost identical to the molecule template. It attaches to
STAT3 in three places. We can optimize celecoxib, and that is expected to
come soon. But applying our technique to find those pieces and determining
that they come from an existing drug makes the discovery process much
faster," said Li, a key co-author of the paper and frequent research
collaborator with Lin.

Li has termed this approach as in silico (computer-driven) drug
repositioning or repurposing.

The discovery that celecoxib can bind to STAT3 also appears to apply to
other cancers. Both Lin and Li were key authors on a recent paper that
suggested that celecoxib's ability to block STAT3's function might also
make it effective as a treatment for rhabdomyosarcoma, the most common soft
tissue cancer in children and adolescents. This research was published in
the April 15 issue of the journal Biochemical and Biophysical Research
Communications.

Co-authors of the liver cancer and rhabdomyosarcoma studies include Yan
Liu, Aiguo Liu and Suzanne Reed of the Center for Childhood Cancer at
Nationwide Children's Hospital (Aiguo Liu is also affiliated with Tongji
Hospital at Huazhong University of Science and Technology in Wuhan, China);
and Huameng Li of Ohio State's Division of Medicinal Chemistry and
Pharmacognosy and the Biophysics Graduate Program.

This work was supported by grants from the National Institutes of Health
and the Department of Defense Congressionally Directed Medical Research
Programs.




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发表于 2011-5-18 03:21 |只看该作者
常见消炎哄着肝癌细胞自杀

科学日报(2011年5月16日) - 抗炎药塞来昔布,已知
西乐葆的品牌名称,触发器,由反应肝癌细胞死亡
用的方式,使这些细胞自杀的蛋白质,根据
一项新的研究。

研究人员还发现,与每个组合的两个昔
化疗药物在杀死肝癌细胞培养更多,使得这些
无论是在组合超过其自己的药物有效。

“每一个单独将减少化疗药物对癌细胞的生长,但
当每个单药是结合西乐葆,一个更大的增长
抑制效果进行了观察,说:“Jiayuh琳,资深作者
儿科研究和俄亥俄州立大学副教授。
“对于临床医生,本研究建议一个新的可能性
治疗策略。“

塞来昔布已通过作用于STAT3的,里面肝癌基因这种效果
细胞被激活后,允许那些抵抗癌细胞的作用
化疗药物。研究人员认定,塞来昔布
分子结合的所谓以STAT3的“热点”,有效地阻断其
运作的能力。

强大的计算技术进行了研究人员之前曾经受雇于
视为一个潜在的治疗癌症的塞来昔布。西乐葆是
非类固醇消炎药物,或类固醇消炎药,使用Cox - 2抑制剂
这意味着它可以帮助控制酶抑制一种称为炎症
环氧合酶-2。这是最常用的处方来治疗疼痛
关节炎。

李乘龙,一个医药化学助理教授
在俄亥俄州立生药学,已开发的电脑模拟来确​​定
片段最佳的药物组合,同时附加的蛋白质
的方式,阻止蛋白质的功能。通过搜索数据库
现有联邦政府批准的药品,他发现昔在结构上
类似模板分子,他已经决定将最
有效地结合STAT3和抑制其功能。

“通常情况下,持续激活STAT3是在癌症细胞。如果你有一个
良好的分子,坚持STAT3的,它会阻止其激活,“李
说。当STAT3的被抑制,细胞的生存途径被封锁
导致癌细胞砍自己和死亡。

这项研究在网络上出现,并为以后计划在印刷出版物
癌症预防研究期刊。

这项研究的生物部分进一步明确了一个角色
前炎症蛋白在肝癌的发展。这种蛋白质被称为
白细胞介素-6,或IL - 6,是一种细胞因子,导致一种化学信使
炎症,它可以在有利和破坏性影响
身体。其他科学家此前的研究表明,高水平的
血液中的白细胞介素-6都与肝癌,最
普通型的肝癌。

林和他的同事确定了IL - 6启动一个化学反应
叫STAT3的磷酸化。这种反应在肝脏STAT3的激活
肿瘤细胞,在反过来激活STAT3的其他已知至少有三
基因,使细胞抵抗化疗的效果。

科学家对肝癌治疗的五个不同类型的
两种不同剂量的塞来昔布两个小时的细胞,并随后
给他们30分钟的IL - 6。前处理与低剂量
塞来昔布抑制IL - 6的能力,开始反应,激活
STAT3的。高剂量完全阻断STAT3的。

然后,研究人员与塞来昔布治疗肝癌细胞系中
结合两种化疗药物:阿霉素,这是用来
治疗乳腺癌,卵巢癌,胃癌,甲状腺及其他一些癌症,
索拉非尼,这是唯一由美国食品药物化疗批准
药品监督管理局治疗肝癌。它的牌子
多吉美。

由于这两种药物,塞来昔布治疗除了数量减少
任何可行的肝肿瘤细胞的大约百分之50以上
百分之九十以上,这取决于剂量。塞来昔布组合,
索拉非尼也大大限制了肿瘤细胞的能力,形成
殖民地,肿瘤的生长的关键要素,药后存活
治疗。

“由于肝癌具有非常低的五年存活率,这是最
索拉非尼甚至可能仅仅可能不能有效地治疗癌症,“
林说,也是一个在俄亥俄州的综合癌症中心研究员
与中心在全国的儿童医院儿童癌症。 “我们
希望这两种药物一起使用能更有效。双方昔
和索拉非尼已被FDA批准,所以我们认为这种组合
治疗应能够在临床运用非常快。“

在人类第五大最常见的癌症,肝癌仍是一
最困难的成功治疗。患者的总体五年生存率
率约​​为百分之十,根据美国癌症协会。

这些实验进行细胞培养。进一步的测试会
需要确定昔在人类癌症的成效,林说。

和强大的计算工作由市里领导,也是一个在俄亥俄州调查
国家综合癌症中心的,很可能导致发展
与更精确的新的分子结构关系
他们的目的是蛋白质块。

李的方法被称为多配体的同步对接。在这项工作中,
他用电脑模拟来识别“热点”的STAT3蛋白
- 小口袋,其中最成功的分子可以附着在
抑制这种蛋白质的活动。然后,他通过药物银行搜查
含有超过7,500现有和实验药物,以找到
了可以拼凑在一起,最合适的分子片段
产生一个新的分子形状的方式,它将适合那些
口袋。

设计一个模板分子后,将最有效地结合
STAT3的,他比较了该模板联邦政府批准的药品1400
已经在市场上。

“昔几乎是相同的分子模板。它重视
STAT3在三个地方。我们可以优化昔,那就是预期
很快到来。但以我们的技术找到这些碎片,并确定
他们从现有的药物发现过程中来,使很多
更快,“李说,一个关键的共同研究论文的作者和频繁
合作者与林。

李称之为这个在硅片(计算机驱动)药物的方法
重新定位或重新利用。

塞来昔布,这一发现可以绑定到STAT3的似乎也适用于
其他癌症。无论林和李键在最近的一篇文章的作者是
建议,塞来昔布的能力阻止STAT3蛋白的功能也可能
使其有效作为横纹肌肉瘤的治疗,最常见的软
癌组织中的儿童和青少年。这项研究结果发表在
4月15日发行的期刊生物化学与生物物理学研究
通讯。

共同作者的肝癌和横纹肌肉瘤研究包括严
刘,刘和爱国的Suzanne为儿童癌症中心里德
全国儿童医院(爱国刘璇也是附属同济
医院在华中武汉,中国)科学和技术大学;
和华盟俄亥俄州的李科药物化学
生药学和生物物理研究所。

这项工作是根据由美国国立卫生研究院的赞助
与国防部,国会导演医学研究
程序。
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