|Study Provides Clues about How Cancer Cells
Develop Resistance to Chemotherapy Drug
Researchers have shown that increased expression of a gene called
SIRT1 in cancer cells plays a significant role in the development
of resistance to the chemotherapy drug cisplatin. The SIRT1 gene,
which regulates several important cellular processes including
nutrient use and metabolism, appears to contribute to the development
of cisplatin resistance by reducing the uptake and use of glucose
by cells and by altering the function of their mitochondria, which
are cellular structures that produce most of the energy in cells.
These findings, by researchers at the National Cancer Institute
(NCI), part of the National Institutes of Health (NIH), and colleagues,
were published in the Sept. 15, 2008, issue of Molecular Cancer
Cisplatin, a chemotherapy drug that contains the metallic element
platinum, is widely used in the treatment of many types of cancer,
including bladder, lung, ovarian, and testicular cancer. It slows
or stops the growth of cancer cells by binding to DNA. Tumors that
recur after an initially positive response to treatment with cisplatin
are frequently resistant to it, meaning the drug is no longer effective.
Knowing more about how cells become resistant to cisplatin will
enable researchers to devise strategies to circumvent resistance
and increase the effectiveness of this important anticancer drug.
To investigate mechanisms that contribute to cisplatin resistance
in cancer cells, the researchers generated cells that were resistant
to the drug by exposing them to cisplatin in the laboratory. They
found that expression of the SIRT1 gene increased three to five
fold as the levels of cisplatin were increased, producing increasing
levels of resistance in the cells. On the other hand, the researchers
found that cisplatin-resistant cancer cells became more sensitive
to the drug when the level of SIRT1 expression was reduced. By
decreasing the levels of SIRT1 expression three to five fold, the
cancer cells became approximately two fold more sensitive to cisplatin." It
appears that SIRT1 contributes to 50 percent of the cellular resistance
to cisplatin, but it does not account for all of the resistance," said
Michael Gottesman, M.D., of NCIís Center for Cancer Research, and
an author of the study.
Many factors contribute to cisplatin resistance and may include
mechanisms that limit cellular uptake of the drug, altered mechanisms
that allow cells to repair damage to their DNA, and mechanisms
that help cells survive. "This study is part of a larger effort
by scientists to determine important cellular changes that cause
cancer cells to become resistant to chemotherapy drugs," said
Gottesman. "Different types of genetic mutations can occur
during the development of cellular resistance to anticancer drugs.
Therefore, the first step is to elucidate the genes that contribute
to this resistance in tumors."
Previous research by this team and others has shown that cisplatin-resistant
cells grow more slowly and demonstrate reduced uptake of certain
substances, including nutrients such as glucose, than cells that
are sensitive to the drug. It was also known that, as a survival
strategy, tumors alter their metabolism when nutrients are scarce.
In this study, the researchers found that cancer cells increased
their expression of SIRT1 and became more resistant to cisplatin
treatment as the level of glucose in their environment was reduced.
They also found that the uptake of glucose in resistant cells was
four to five fold less than in cells that were sensitive to cisplatin.
Oxygen consumption, an indicator of glucose use and energy production,
decreased by 30 percent to 60 percent compared to cisplatin-sensitive
Because mitochondria use glucose and oxygen to produce energy,
the team investigated the function of mitochondria in cisplatin-resistant
cells. They found that, as cellular resistance to cisplatin increased,
the potential of mitochondria to produce energy decreased, indicating
that the metabolic role of mitochondria in resistant cells is different
from that in cells that are sensitive to the drug. The researchers
also found that the mitochondria of resistant cells were smaller
and that the internal structures were irregular compared to the
mitochondria of cells that were sensitive to the drug.
Gottesman and colleagues are developing molecular tools to define
the drug-resistance genes that are expressed in individual cancers,
and, in the future, hope to use this information to predict a patientís
response to therapy and to design new ways to circumvent resistance.
In addition to NCI, researchers from the National Heart, Lung,
and Blood Institute, part of the NIH; the U.S. Food and Drug Administration;
and the National Center of Nanoscience and Technology, Beijing,
Peopleís Republic of China, participated in the study.
For more information on Dr. Gottesmanís research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5713.
NCI leads the National Cancer Program and the NIH effort to dramatically
reduce the burden of cancer and improve the lives of cancer patients
and their families, through research into prevention and cancer
biology, the development of new interventions, and the training
and mentoring of new researchers. For more information about cancer,
please visit the NCI Web site at http://www.cancer.gov or
call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: Liang X, Finkel T, Shen D, Yin J, Aszalos
A., and Gottesman MM. SIRT1 Contributes in Part to Cisplatin Resistance
in Cancer Cells by Altering Mitochondrial Metabolism. Molecular
Cancer Research. September, 15, 2008.