February 1, 2003

Alakananda Basu, PhD, deputy director of the Institute for Cancer Research at UNT Health Science Center, investigates how cells communicate to better understand how cancer develops and learn to treat it more effectively. She hopes to improve the efficacy of chemotherapy by exploiting a cellâ??s signaling, or communication, pathways.

To control growth, cells communicate with each other and their environment through a network of signaling systems. Through a process called signal transduction, cells receive signals that tell them when to divide and when to die, said Dr. Basu, who is also an associate professor of molecular biology and immunology.

Cell death, or apoptosis, is important because it removes unwanted or damaged cells from the body. Because too little cell death can lead to cancer, it plays an important role in the development and progression of cancer. Apoptosis can also influence the response of tumor cells to cancer therapy since most anticancer medication works by ultimately inducing cell death, Dr. Basu said. Understanding what controls it is an important step to developing more effective treatments. â??In normal cases, thereâ??s a perfect balance between cell death and growth. With cancer, this balance is disrupted,â? she explained.

Dr. Basuâ??s research focuses on protein kinase C (PKC), a critical signaling element regulating cell growth. PKC belongs to a family of related proteins with distinct roles in the body, and she has shown in breast cancer models that some members of the PKC family can disrupt the process of cell death.

Dr. Basu is investigating how PKC interacts with tumor necrosis factor-alpha (TNF) in this process. TNF is a small protein, or cytokine, that influences cell communication.â??TNF regulates a wide variety of cellular functions,â? Dr. Basu said. â??It is involved in cell growth and death, as well as cell differentiation, the process by which cells take on unique characteristics.â? It also plays an important role in immunosurveillance, the monitoring process the immune system uses to recognize and destroy cancer cells, she said.

â??TNF begins the process of cell death by binding, or interacting, with receptors on the cellâ??s surface,â? Dr. Basu explained. â??This interaction triggers the activation of a family of killer proteins, or caspases, that are essential for the execution of cell death by apoptosis.â? She is trying to determine how PKC regulates the activation of caspases and whether it cooperates with other cellular signaling systems to inhibit apoptosis.

â??Because too little cell death can lead to the development and progression of cancer, an understanding of how PKC prevents cell death should allow researchers to develop ways to use signaling pathways to inhibit the development of cancer,â? she said. â??The ultimate goal is to exploit PKC signal transduction pathways to benefit cancer therapy.â?

Traditional forms of chemotherapy, such as drug therapy, have several disadvantages that limit their value, she said. When the concentration of chemotherapy drugs is increased to treat unresponsive tumors, the medication can become toxic. In addition, patients often develop resistance to anticancer drugs and traditional medications may not be equally effective on all types of cancer.

Dr. Basu has been using the anticancer drug cisplatin as a model. Cisplatin is used to treat several types of cancer, including ovarian, testicular, cervical and small cell lung cancers. It works by binding to the DNA and preventing cells from dividing, Dr. Basu said.

Ideally, chemotherapy strives to eradicate only cancer cells without affecting healthy cells; however, cisplatin and other anticancer drugs can also bind with the DNA of healthy cells, causing the medicine to become toxic.

â??Furthermore, when cancer cells become resistant to cisplatin, the PKC signal transduction pathway is compromised,â? she said. â??I hope to determine how these changes in PKC influence the activation of caspases and contribute to drug resistance. That will allow us to develop strategies to circumvent resistance to cisplatin.â? In addition to investigating how to combat resistance, Dr. Basu is also working to improve the efficacy of chemotherapy. She has shown that cisplatin can more effectively kill cancer cells when combined with agents that affect the PKC signal transduction pathway, such as a marine compound called bryostatin 1.

Clinical trials have begun for bryostatin 1, which targets PKC. When used alone, bryostatin 1 had limited success, however, Dr. Basu has shown that when used in small amounts in conjunction with cisplatin, it substantially improved the ability of cisplatin to kill cervical cancer cells.â??PKC regulators such as bryostatin 1 can regulate cell death by influencing the activity of the killer proteins, or caspases, which are activated by substances that damage DNA, such as anticancer medication,â? she explained. As a result of her research, the National Institutes of Health has begun clinical trials studying bryostatin 1 and cisplatin. â??Regulation of PKC by bryostatin 1 is complex, and a thorough understanding of how PKC regulates cell death is important to use bryostatin 1 effectively for cancer therapy,â? Dr. Basu said.

Currently, her laboratory is trying to determine what steps leading to cell death occur following cisplatin-induced DNA damage. Dr. Basu is also studying how the PKC signal transduction pathway regulates how sensitive cells are to cisplatin.

While she uses cisplatin as a model drug, Dr. Basu expects her research will also be applicable to other drugs and disorders. When the processes regulating cell death malfunction, other diseases, such as neurodegenerative disorders and heart disease, can result, she said. This makes understanding how cell death works important to the treatment of many other diseases.

Dr. Basuâ??s projects on TNF and PKC, â??Tumor necrosis factor-alpha signaling in breast cancerâ? and â??Signal transduction and cell death regulation,â? are both funded by the National Institutes of Health.

Prior to joining the health science center, Dr. Basu was an assistant professor in the department of pharmacology at the University of Pittsburgh, where she also served as a member of the Pittsburgh Cancer Institute. She earned a bachelorâ??s in chemistry and a masterâ??s in biochemistry from the University of Calcutta in India and earned a doctorate in biochemistry from the University of Pittsburgh.


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