Featured Research

from universities, journals, and other organizations

Anti-cancer Drugs May Hold Promise For Premature Aging Disorder

Date:
August 30, 2005
Source:
NIH/National Human Genome Research Institute
Summary:
In a surprising development, a research team led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), has found that a class of experimental anti-cancer drugs also shows promise in laboratory studies for treating a fatal genetic disorder that causes premature aging.

Megan, 5 (Progeria patient).
Credit: Photo courtesy of The Progeria Research Foundation

BETHESDA, Md., Mon., Aug. 29, 2005 -- In a surprising development, aresearch team led by the National Human Genome Research Institute(NHGRI), part of the National Institutes of Health (NIH), has foundthat a class of experimental anti-cancer drugs also shows promise inlaboratory studies for treating a fatal genetic disorder that causespremature aging.

In a study published Monday in the online edition of the Proceedingsof the National Academy of Sciences (PNAS), Brian Capell and hiscolleagues at NHGRI reported that drugs known as farnesyltransferaseinhibitors (FTIs), which are currently being tested in people withmyeloid leukemia, neurofibromatosis and other conditions, might alsoprovide a potential therapy for children suffering fromHutchinson-Gilford Progeria Syndrome, commonly referred to as progeria.A related study from Stephen Young, M.D., and colleagues at theUniversity of California at Los Angeles is being published in the sameissue of PNAS.

There are currently no treatments for progeria, which is agenetic disorder estimated to affect one child in 4 million. When theyare born, children with progeria appear normal. But, as they growolder, they experience growth retardation and show dramaticallyaccelerated symptoms of aging -- namely hair loss, skin wrinkling andfat loss. Accelerated cardiovascular disease also ensues, typicallycausing death from heart attack or stroke at about the age of 12.

"Our findings show that FTIs, originally developed for cancer,are capable of reversing the dramatic nuclear structure abnormalitiesthat are the hallmark of cells from children with progeria. This is astunning surprise, rather like finding out that the key to your housealso works in the ignition of your car," said NHGRI Director Francis S.Collins, M.D., Ph.D., who is the study's senior author.

The new work involved using FTIs to treat skin cells taken fromprogeria patients and grown in laboratory conditions. If upcomingstudies in a mouse model validate the results of the cell experimentsand translate into improvements in the animals' conditions, a clinicaltrial of FTIs in children with progeria may begin as early as nextspring, researchers said.

Dr. Collins and his colleagues discovered in April 2003 thatmutations in the lamin A (LMNA) gene cause progeria, spurring renewedinterest among researchers to study this rare syndrome. Among thosewere Capell, a New York University medical student participating in theHoward Hughes Medical Institute/NIH (HHMI/NIH) Research ScholarsProgram. In July 2004, he joined Dr. Collins' lab and immediately sethis sights on understanding the molecular basis of progeria.

"What really interested me in this research in the first placewere the potential links to aging and atherosclerotic disease," saidCapell. Indeed, understanding progeria at the molecular level mayilluminate the general processes involved in normal human aging.

The LMNA gene codes for a protein called lamin A, whichconstitutes a major component of the scaffold-like network of proteinsjust inside the cell's nuclear membrane, called the lamina. The genemutation implicated in progeria causes a section of 50 amino acidswithin the lamin A protein to be deleted, resulting in a mutatedprotein that is called progerin. This protein fails to integrateproperly into the lamina, thereby disrupting the nuclear scaffoldingand causing gross disfigurement of the nucleus. Cells with progerinhave a nucleus with a characteristic "blebbed," or lobular, shape.

To find its way to the lamina, lamin A carries two tags,rather like ZIP codes, that help to direct the protein's travels. Onetag at the end of lamin A instructs another protein to modify itthrough a process called farnesylation. Farnesylation tethers lamin Ato the inner nuclear membrane. Once there, a second tag within theprotein signals an enzyme to cleave off the terminal portion of theprotein, including the farnesyl group, freeing lamin A to integrateproperly into the nuclear lamina.

Because progerin carries the farnesylation tag but lacks thesecond cleavage tag, Capell speculated that progerin was becomingpermanently stuck to the inner nuclear membrane. There, he suspected,it enmeshed other scaffolding proteins, preventing their properintegration into the lamina. If progerin's tendency to stick to theinner nuclear membrane is indeed the culprit in nuclear blebbing andthe root of the progeria defect, Capell and his colleagues reasonedthat they could prevent these defects by blocking farnesylation ofprogerin.

The researchers' hunch proved correct. When they changed oneamino acid within progerin's farnesylation tag to prevent the additionof a farnesyl group and tested the effect in cells grown in thelaboratory, progerin did not anchor itself to the inner nuclearmembrane and instead clumped within the nucleus. Moreover, theyobserved no nuclear blebbing.

The researchers then tried treating the cells carrying progerinwith FTIs, which are drugs originally developed to inhibit certaincancer-causing proteins that require farnesylation for function. FTIsare now being tested in phase III clinical trials of patients withmyeloid leukemia. So far, clinical trials using FTIs have found littletoxicity, even when the drug treatment significantly raises levels ofunfarnesylated proteins.

After FTI treatment, the progerin-carrying cells showed noblebbing. More importantly, researchers saw the same effect when theyused FTIs to treat cells grown from skin biopsies of progeria patients:Cell blebbing decreased to near normal levels.

In addition to Capell and his colleagues in NHGRI's GenomeTechnology Branch, researchers from the University of North Carolina atChapel Hill and the University of Michigan School of Public Health inAnn Arbor took part in the study.

The HHMI/NIH Research Scholars Program gives outstandingmedical and dental students the opportunity to conduct biomedicalresearch under the direct mentorship of senior NIH research scientists.

###

NHGRI is one of the 27 institutes and centers at NIH, which is anagency of the Department of Health and Human Services. The NHGRIDivision of Intramural Research develops and implements technology tounderstand, diagnose and treat genomic and genetic diseases. Additionalinformation about NHGRI can be found at its Web site: www.genome.gov.


Story Source:

The above story is based on materials provided by NIH/National Human Genome Research Institute. Note: Materials may be edited for content and length.


Cite This Page:

NIH/National Human Genome Research Institute. "Anti-cancer Drugs May Hold Promise For Premature Aging Disorder." ScienceDaily. ScienceDaily, 30 August 2005. <www.sciencedaily.com/releases/2005/08/050830065132.htm>.
NIH/National Human Genome Research Institute. (2005, August 30). Anti-cancer Drugs May Hold Promise For Premature Aging Disorder. ScienceDaily. Retrieved August 20, 2014 from www.sciencedaily.com/releases/2005/08/050830065132.htm
NIH/National Human Genome Research Institute. "Anti-cancer Drugs May Hold Promise For Premature Aging Disorder." ScienceDaily. www.sciencedaily.com/releases/2005/08/050830065132.htm (accessed August 20, 2014).

Share This




More Health & Medicine News

Wednesday, August 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Possible Ebola Patient in Isolation at California Hospital

Possible Ebola Patient in Isolation at California Hospital

Reuters - US Online Video (Aug. 20, 2014) — A patient who may have been exposed to the Ebola virus is in isolation at the Kaiser Permanente South Sacramento Medical Center. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
Raw: World's Oldest Man Lives in Japan

Raw: World's Oldest Man Lives in Japan

AP (Aug. 20, 2014) — A 111-year-old Japanese was certified as the world's oldest man by Guinness World Records on Wednesday. Sakari Momoi, a native of Fukushima in northern Japan, was given a certificate at a hospital in Tokyo. (Aug. 20) Video provided by AP
Powered by NewsLook.com
Do More Wedding Guests Make A Happier Marriage?

Do More Wedding Guests Make A Happier Marriage?

Newsy (Aug. 20, 2014) — A new study found couples who had at least 150 guests at their weddings were more likely to report being happy in their marriages. Video provided by Newsy
Powered by NewsLook.com
Ebola-Hit Sierra Leone's Freetown a City on Edge

Ebola-Hit Sierra Leone's Freetown a City on Edge

AFP (Aug. 19, 2014) — Residents of Sierra Leone's capital voice their fears as the Ebola virus sweeps through west Africa. Duration: 00:56 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins