|HIV Protease Inhibitors Show Potential as Cancer
Several protease inhibitors that are used in combination with
other drugs to treat Human Immunodeficiency Virus (HIV) infection
may also be effective against certain types of cancer, according
to researchers from the National Cancer Institute (NCI), part of
the National Institutes of Health. Nelfinavir (Viracept®),
Ritonavir (Norvir®), and Saquinavir (Invirase®) inhibited
growth of several types of cancer cells, with Nelfinavir being
the most effective. These results appear in the September 1, 2007
issue of Clinical Cancer Research.
The NCI research team investigated HIV protease inhibitors because
these drugs are known to inhibit the activation of Akt, a protein
that has been implicated in the development of many types of cancer,
including non-small cell lung cancer. Using mouse models and in
vitro studies, the researchers tested six different protease
inhibitors against non-small cell lung cancer as well as a panel
of 60 human cancer cell types, in cultures (called cell lines)
derived from nine different kinds of malignant tissue. When given
in doses that were previously proven to be safe in HIV-infected
patients, three of the six protease inhibitors (nelfinavir, ritonavir
and saquinavir) inhibited growth of non-small cell lung cancer
and every cell type in the set of 60 kinds of cancer cells.
"There are many common threads between cancer and HIV/AIDS,
and this research underscores the value of NCIís involvement in
HIV/AIDS research," said NCI Director John E. Niederhuber,
In this study, nelfinavir and saquinavir were more potent than
the other HIV protease inhibitors examined. They each had similar
abilities to prevent tumor growth, and induce programmed cell death,
or apoptosis, which is a normal process that rids the body of old
or damaged cells. The molecular structures of these two drugs share
a trait that is not found in the other drugs that were tested,
and the researchers speculate that this trait might provide an
explanation for the relatively higher potency of these two drugs.
Nelfinavir was the most effective of all the protease inhibitors
tested, and was able to cause two different types of cancer cell
death—apoptosis and non-apoptotic cell death.
In this study, non-apoptopic cell death was related to induction
of stress on part of the cell that synthesizes proteins called
the endoplasmic reticulum (ER), which subsequently led to autophagy,
a normal process of self digestion that generates energy for the
cell under conditions of stress. In the past, other anti-cancer
agents have been shown to induce either ER stress or autophagy
in a test tube, but in this study nelfinavir was also able to initiate
this process in cells that had been transplanted into mice. Other
studies have also shown that nelfinavir could induce apoptosis,
but non-apoptopic cell death via nelfinavir was a new discovery.
"ER stress and autophagy are cellular processes that are
gaining importance in cancer research because we suspect that impaired
autophagy may contribute to cancer development," said Niederhuber. "Markers
of ER stress and autophagy will be useful biomarkers for nelfinavir
as its clinical development proceeds."
Nelfinavir was successful in inhibiting growth of both drug-sensitive
and drug-resistant breast cancer cells, indicating that this drug
could be useful against cancer cells that have acquired resistance
to common anti-cancer therapies, such as tamoxifen and trastuzumab.
There is also evidence that use of nelfinavir may be able to overcome
resistance to radiation.
Based on the results of this study, senior investigator, Phillip
A. Dennis, M.D., Ph.D., from the Medical Oncology Branch of the
NCI Center for Cancer Research, and his colleagues have just begun
a new clinical trial to test nelfinavir in cancer patients. This
trial will determine how much of the drug can be tolerated by cancer
patients (toxicity), and how the drug behaves in the body and reacts
with the tumors (pharmacokinetics).
The process of identifying new indications for already approved
drugs, called repositioning, takes advantage of existing data on
toxicity, pharmacokinetics, and potential side effects. There are
several successful examples of this approach, including the use
of COX-2 inhibitors (anti-inflammatory drugs) for colon cancer
prevention and lenalidomide (a morning sickness drug) for myelodysplastic
syndromes. NCI researchers are currently conducting other repositioning
studies using rapamycin (an immunosuppressant) and medroxyprogesterone
acetate (a birth-control hormone). Drug repositioning could complement
new drug development, with decreased risks and reduced costs.
"The need for expedited development of effective cancer therapies
is critical," said Dennis. "Repositioning drugs that
are already FDA-approved for use in humans could greatly accelerate
the development of new cancer therapies. Our data suggest that,
given its wide spectrum of activity and ability to be administered
through two different transmission routes [oral and intraperitoneal],
nelfinavir could be successfully repositioned as a cancer therapeutic."
For more information about cancer, 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).
For more information on Dr. Dennisís research, go to http://ccr.cancer.gov/Staff/Staff.asp?profileid=5727.
For more information about the new Phase I trial of Nelfinavir
at the NIH Clinical Center, please visit http://bethesdatrials.cancer.gov/solid_tumor/nci07c0047/default.asp
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and supporting basic, clinical and translational medical research,
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