HIV Protease Inhibitors Show Potential as Cancer Treatments in Preclinical Studies
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 lab studies (called in vitro studies) and mouse models, 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 NCI’s involvement in HIV/AIDS research,” said NCI Director John E. Niederhuber, M.D.
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, indicating that 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.”
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Gills JJ, LoPiccolo J, Tsurutani J, Shoemaker RH, Best CJM, Abu-Asab MS, Borojerdi J, Warfel NA, Gardner ER, Danish M, Hollander MC, Kawabata S, Tsokos M, Figg WD, Steeg PS, and Dennis PA. Nelfinavir, a lead HIV protease inhibitor, is a broad spectrum, anticancer agent that induces ER stress, autophagy and apoptosis in vitro and in vivo. Clin Can. Res. Vol. 13, No. 17. September 1, 2007.
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. Dennis’s 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