||Researchers at the University
of Pennsylvania School of Medicine have
found that a commonly prescribed diabetes drug kills
tumor cells that lack a key regulatory gene called p53.
||Metformin activates the metabolic enzyme
AMPK (AMP activated protein kinase), which exerts changes
on cellular metabolism by affecting p53 function.
Two observational studies already show that diabetic patients
who take metformin have a lower rate of cancer diagnosis
and mortality than other diabetics.
||The researchers found that metformin
instructs cells to switch metabolic pathways. Instead of
using the most energy efficient pathway – called oxidative
phosphorylation – the cells are forced to use stress-related
ones, which are typically used when the cell is short on
oxygen, glucose or other nutrient sources. But in the absence
of p53, the cells can’t make the switch.
||The Penn team reported their findings
last month in Cancer
(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine have found that a commonly prescribed diabetes drug kills tumor cells that lack a key regulatory gene called p53.
Results from current studies in mice may result in new therapies
for a subset of human cancers that tend to be aggressive and resistant
to existing treatments. Additionally, the findings open up a new
avenue for targeting cancers whose hallmark is the absence of this
The Penn team reported their findings last month in Cancer
“This is the first time you can show that tumor growth is impaired
by a diabetes drug,” says senior author Craig
B. Thompson, MD,
Director of the Abramson Cancer Center and Chairman and Professor of
Cancer Biology and Medicine. “It is specific for tumors that lack
p53, which is the most common mutation in human cancer.”
More than half of all human cancers have lost the p53 gene. Yet even
in an era of molecularly targeted therapies scientists have had trouble
figuring out how to compensate for the absence of a gene. Unlike a genetic
mutation that changes the function or activity of a gene, which can be
inhibited by a well-tailored drug, loss of a gene leaves nothing for
the drug to target.
Thompson and his team, however, have been accumulating evidence over
the last several years that p53, best known as a regulator of cell
controls several metabolic pathways in cells. For potential cancer therapies,
that means a drug that affects pathways controlled by p53 could help
control p53-deficient tumors.
Significantly, the regulation of metabolic pathways by p53 is also influenced
by metformin, the most widely used diabetes drug. Metformin activates
the metabolic enzyme AMPK (AMP activated protein kinase), which exerts
changes on cellular metabolism by affecting p53 function. Two observational
studies already show that diabetic patients who take metformin have a
lower rate of cancer diagnosis and mortality than other diabetics.
Thompson’s group hypothesized that metformin may specifically
slow the growth of cancers that lack p53. To find out, they injected
human colon cancer cells that have normal p53 function into one side
of mice and colon cancer cells that lack p53 into the other side. Four
days later they started treating the animals with a daily injection of
either a saline control solution or with metformin, using a dose comparable
to diabetic treatment in humans.
Four weeks later, the p53-deficient tumors in mice treated with
metformin were half the size of the p53 deficient tumors in control mice.
There was no difference in the size of the p53 normal tumors between
the animals treated with metformin or saline. They concluded that metformin
slowed the growth of the colon cancer cells that lack a normal p53 function.
The researchers found that metformin instructs cells to switch metabolic
pathways. Instead of using the most energy efficient pathway – called
phosphorylation – the cells are forced to use stress-related
ones, which are typically used when the cell is short on oxygen, glucose or other nutrient sources. But in the absence of p53, the cells can’t
make the switch. “Without p53, if we force cells to live on alternative
substrates, they can’t do it,” explains Thompson.
Thompson’s team is now working with collaborators to decide how
best to translate these novel observations into clinical practice. If
preclinical tests continue to look promising, development of metformin
as a cancer therapy may move quickly as the drug is already approved
by U.S. Food and Drug Administration for use in humans, the researchers
The study was funded by grants from the National
Buzzai, a graduate student in Thompson’s lab, is first
author on the study. Co-authors include Russell
Jones, Julian Lum, and Ralph DeBerardinis from Penn; Ravi
Amaravadi and Fangping Zhao from Penn and The Children’s
Hospital of Philadelphia; and Benoit Viollet
from the Centre National
de la Recherche Scientifique and Inserm.
The Abramson Cancer Center (ACC) of
the University of Pennsylvania is a national
leader in cancer research, patient care, and education. The
pre-eminent position of the Cancer Center is reflected in
its continuous designation as a Comprehensive Cancer Center
by the National Cancer Institute for 30 years, one of 39
such Centers in the United States. The ACC is dedicated to
innovative and compassionate cancer care. The clinical program,
comprised of a dedicated staff of physicians, nurse practitioners,
nurses, social workers, physical therapists, nutritionists
and patient support specialists, currently sees over 50,000
outpatient visits, 3400 inpatient admissions, and provides
over 25,000 chemotherapy treatments, and more than 65,000
radiation treatments annually. Not only is the ACC dedicated
to providing state-of-the-art cancer care, the latest forms
of cancer prevention, diagnosis, and treatment are available
to our patients through clinical themes that developed in
the relentless pursuit to eliminate the pain and suffering
from cancer. In addition, the ACC is home to the 300 research
scientists who work relentlessly to determine the pathogenesis
of cancer. Together, the faculty is committed to improving
the prevention, diagnosis and treatment of cancer.
PENN Medicine is
a $3.5 billion enterprise dedicated to the related missions
of medical education, biomedical research, and excellence in
patient care. PENN Medicine consists of the University of Pennsylvania
School of Medicine (founded in 1765 as the nation's first medical
school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #3 in the
nation in U.S.News & World Report's survey of top research-oriented
medical schools; and, according to most recent data from the
National Institutes of Health, received over $379 million in
NIH research funds in the 2006 fiscal year. Supporting 1,400
fulltime faculty and 700 students, the School of Medicine is
recognized worldwide for its superior education and training
of the next generation of physician-scientists and leaders of
The University of Pennsylvania Health System includes
three hospitals — its flagship hospital,
the Hospital of the University of Pennsylvania, rated one of
the nation’s “Honor Roll” hospitals by U.S.News & World
Report; Pennsylvania Hospital, the nation's first hospital; and
Penn Presbyterian Medical Center — a
faculty practice plan; a primary-care provider network; two multispecialty
satellite facilities; and home care and hospice.