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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 03:18