(Press-News.org) COLUMBUS, Ohio – Scientists have found that a synthetic molecule they designed can block activation of a gene in liver cancer cells, halting a process that allows some of those cancer cells to survive chemotherapy.
Without the interference of this gene's function, certain liver cancer cells appear to be protected from the toxic effects of chemotherapy drugs.
Blocking the oncogene, called STAT3, prevents a protein from protecting the cells, the research suggests. As a result, more liver cancer cells succumb to treatment.
Researchers hope an anti-cancer drug based on the molecule's design eventually will be developed for use in patients, after the required animal and clinical testing is completed.
The scientists have seen similar results in studies using this experimental molecule, called LLL12, to block STAT3 as a way to induce cell death in breast and pancreatic cancer cells.
"For patients, it would be easy to use an intravenous drug based on this small molecule, which is relatively cheap and easy to manufacture," said Jiayuh Lin, senior author of the study and an associate professor of pediatrics at Ohio State University.
"We also have seen signs that blocking STAT3 could block other downstream targets, and could affect other STAT3-regulated genes that can turn normal cells into cancer cells. We believe this molecule has a lot of potential for cancer therapy."
Lin led the team of scientists who designed LLL12 using powerful computers and a computational method called structure-based design. The group reported on its creation earlier this year.
This new study is published in a recent issue of the Journal of Biological Chemistry.
The protein in this process is called interleukin-6, or IL-6. It is a cytokine, a chemical messenger that causes inflammation, and 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.
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.
In this study, the researchers observed that liver cancer cells known to be resistant to a common chemotherapy drug, doxorubicin, had higher levels of IL-6 than did other liver cancer cells – an indication that the protein likely fosters the drug resistance. Subsequent tests showed that these resistant cells with high IL-6 also had higher levels of STAT3 phosphorylation than did other cells.
To further demonstrate this relationship between the protein and cell survival, Lin and colleagues pretreated liver cancer cells with the chemotherapy drug and then followed with different doses of IL-6. The addition of IL-6 rescued these cells from chemo-induced death.
Alternately, when the scientists introduced an antibody to inhibit IL-6 in drug-resistant cancer cells and then followed with doses of doxorubicin, 70 percent more of the cells treated with the IL-6 inhibitor died compared to cells treated with the chemo drug alone – a sign that the loss of IL-6 lowers survival in these particular cancer cells.
After determining in cell cultures that IL-6 activates STAT3 to help perform this cell survival function, the researchers focused on testing the effects of blocking the gene alone.
They first used silencing RNA, or siRNA, to prevent activation of the STAT3. More of the siRNA-treated cells died than did cells in which the STAT3 was not blocked.
"At this point, we know that STAT3 plays an important role, and that IL-6 depends on STAT3 to protect cells from dying," said Lin, also an investigator in Ohio State's Comprehensive Cancer Center and the Center for Childhood Cancer at Nationwide Children's Hospital.
The scientists then turned to the synthetic molecule, LLL12, which was designed specifically to tuck itself into a gap in STAT3's two-part structure and disable its activation.
The researchers introduced LLL12 to four types of liver cancer cells and followed with a dose of IL-6. The IL-6 protein had no protective effect on cells treated with the molecule, meaning it could not turn on STAT3, a required step in protecting the cells from death.
To be sure, they also tested how cells with and without LLL12 treatment responded to chemotherapy. The small molecule treatment completely blocked resistance to the drug, Lin said, even in the types of liver cancer cells that express the highest IL-6 levels and are most resistant to doxorubicin.
Importantly, the researchers were able to determine that inhibiting STAT3 activation did not affect other proteins that are induced by IL-6 for potentially beneficial reasons. The small molecule also did not exacerbate the effects of chemotherapy on normal liver cells.
Lin and colleagues are currently testing the effects of LLL12 in multiple myeloma, breast and colon cancer cells, in which the IL-6/STAT3 pathway also plays an important role.
INFORMATION:
This work was supported by the grants from the National Institutes of Health, the Pancreatic Cancer Action Network – American Association of Cancer Research, and the National Foundation for Cancer Research.
Co-authors of the study include Yan Liu of the Department of Pediatrics, and Pui-Kai Li and Chenglong Li of the Division of Medicinal Chemistry and Pharmacognosy, all at Ohio State.
Contact: Jiayuh Lin, (614) 722-5086; lin.674@osu.edu
Written by Emily Caldwell, (614) 292-8310; caldwell.151@osu.edu
Blocking an oncogene in liver cancer could be potential therapy option
2010-10-13
ELSE PRESS RELEASES FROM THIS DATE:
Metabolic status before pregnancy predicts subsequent gestational diabetes
2010-10-13
OAKLAND, Calif. — Cardio-metabolic risk factors such as high blood sugar and insulin, and low high density lipoprotein cholesterol that are present before pregnancy, predict whether a woman will develop diabetes during a future pregnancy, according to a Kaiser Permanente study in the current issue of the American Journal of Epidemiology.
The study suggests that metabolic screening of all women before pregnancy, particularly overweight women, could help identify those more likely to develop gestational diabetes mellitus, known as GDM, in a subsequent pregnancy and help ...
Hospital readmission studies: Influencing factors identified
2010-10-13
In two studies published today in the Journal of Hospital Medicine, the risk factors for readmission to the hospital are examined based upon general medicine inpatients and those with at least two admissions in a six-month period. Alongside clinical factors such as having cancer, chronic diseases such as heart failure or lung disease, or being on high-risk medications, the studies identified other factors which increase the likelihood of a patient being readmitted which could help hospitalists focus in on these groups.
In the first study, Nazima Allaudeen, MD, and colleagues ...
Freemake: First CUDA-Supported Free Video Converter
2010-10-13
Freemake Video Converter (http://www.freemake.com/free_video_converter) has recently integrated CUDA technology that can speed up the conversion process by many times. Thus, the videos can be converted to AVI, iPod, iPhone, PSP, and Android devices in a few minutes instead of hours.
Freemake Video Converter, version 1.2, features much higher conversion speed and significant gains in performance due to CUDA technology. Therefore, this free converter can be considered one of the pioneers among video tools.
Now PC users can convert long videos to HD formats much faster ...
Is infertility more common in women with epilepsy?
2010-10-12
ST. PAUL, Minn. – Women with epilepsy may be more likely to experience infertility, according to new research published in the October 12, 2010, print issue of Neurology®, the medical journal of the American Academy of Neurology.
The study of women in India found that women with epilepsy experienced infertility at more than twice the rate of that found in the general population. The research also found that women who were taking multiple epilepsy drugs were more likely to be infertile than those taking fewer drugs or no drugs for epilepsy.
The study involved 375 women ...
You don't have to go out into the woods anymore
2010-10-12
"You don't have to go out into the woods anymore," says tick expert Brian F. Allan, PhD, who just completed a postdoctoral appointment at Washington University in St. Louis. "The deer are bringing tick-borne disease to us."
So, it stands to reason that anything deer like, might increase the risk of tick-borne disease for people.
The invasive plant bush honeysuckle, for example.
Yes, that leafy shrub with the lovely egg-shaped leaves on arching branches, fragrant white or yellow flowers and the dark red berries so attractive to birds.
Called bush or Amur honeysuckle, ...
Microbial hair: It's electric
2010-10-12
Some bacteria grow electrical hair that lets them link up in big biological circuits, according to a University of Southern California biophysicist and his collaborators.
The finding suggests that microbial colonies may survive, communicate and share energy in part through electrically conducting hairs known as bacterial nanowires.
"This is the first measurement of electron transport along biological nanowires produced by bacteria," said Mohamed El-Naggar, assistant professor of physics and astronomy at the USC College of Letters, Arts and Sciences.
El-Naggar was ...
Too much light at night at night may lead to obesity, study finds
2010-10-12
COLUMBUS, Ohio – Persistent exposure to light at night may lead to weight gain, even without changing physical activity or eating more food, according to new research in mice.
Researchers found that mice exposed to a relatively dim light at night over eight weeks had a body mass gain that was about 50 percent more than other mice that lived in a standard light-dark cycle.
"Although there were no differences in activity levels or daily consumption of food, the mice that lived with light at night were getting fatter than the others," said Laura Fonken, lead author of ...
Population trends: Another influence on climate change
2010-10-12
BOULDER--Changes in population growth and composition, including aging and urbanization, could significantly affect global emissions of carbon dioxide over the next 40 years, according to a new study out next week.
The research, appearing in Proceedings of the National Academy of Sciences (PNAS), was conducted by an international team of scientists from the National Center for Atmospheric Research (NCAR), the International Institute for Applied Systems Analysis (IIASA), and the National Oceanographic and Atmospheric Administration. It was funded by a European Young Investigator's ...
Microchip technology rapidly identifies compounds for regrowing nerves in live animals
2010-10-12
CAMBRIDGE, Mass. -- Scientists have long sought the ability to regenerate nerve cells, or neurons, which could offer a new way to treat spinal-cord damage as well as neurological diseases such as Alzheimer's or Parkinson's. Many chemicals can regenerate neurons grown in Petri dishes in the lab, but it's difficult and time-consuming to identify those chemicals that work in live animals, which is critical for developing drugs for humans.
Engineers at MIT have now used a new microchip technology to rapidly test potential drugs on tiny worms called C. elegans, which are often ...
Landing lights for bumblebees
2010-10-12
VIDEO:
Gardeners could help maintain bumblebee populations by growing plants with red flowers or flowers with stripes along the veins, according to field observations of the common snapdragon, Antirrhinum majus, at...
Click here for more information.
Gardeners could help maintain bumblebee populations by growing plants with red flowers or flowers with stripes along the veins, according to field observations of the common snapdragon, Antirrhinum majus, at the John Innes Centre ...