"This finding shows, for the first time, that cancer cells are unusually sensitive to dying by necrosis, when their ability to metabolize glucose is blocked," said Craig Thompson, MD, Principal Investigator of the study and Scientific Director of the Abramson Family Cancer Research Institute (AFCRI). "Up until now, research has focused on finding ways to program cancer cells to die through apoptosis – a very regulated, orderly form of cell death that does not trigger an immune response. Now, we know that cancer cells can be forced to die, suddenly, through necrosis. If we can harness this method, which does trigger an immune response, then, the door will be opened to a whole new and less toxic way to treat cancer."
Despite long-term use, the action of chemotherapeutic agents – to kill and stop the growth of cancer cells – is not well understood. The agents have proven to be effective treatments even for tumors lacking the genes considered essential for apoptosis, but the precise cellular mechanism for this has remained unexplained up until now.
To study this issue, the researchers created mouse cells that were unable to die by apoptosis. The cells were engineered to be deficient in either the tumor suppressor gene p53, the most commonly mutated gene in human cancer, or two key proteins essential for the execution of apoptotic cell death, Bax and Bak. The researchers then determined whether any standard chemotherapeutic drugs could kill these cells. They discovered that some commonly used chemotherapeutic drugs – alkylating agents such as mechlorethamine hydrochloride (nitrogen mustard) – retained the ability to kill the cells engineered to be resistant to apoptosis. When exposed to alkylating agents, the cancer cells died by necrosis, a form of cell death that results from energy depletion.
Of equal importance, the researchers found that the induced necrotic cell death was specific to proliferating cancer cells. The rapid energy depletion was triggered by activation of a DNA repair protein, called PARP. Its activation leads to an inhibition of the cancer cell's ability to break down glucose to produce the cellular fuel ATP, a process termed glycolysis. In contrast, non-proliferating or non-cancerous cells did not exhibit energy depletion, as they produce most of their ATP by metabolizing a mixture of fats, proteins, and carbohydrates in a process termed oxidative phosphorylation. This explains why necrotic cell death, induced by the chemotherapeutic agents, was specific to cancer cells and did not affect healthy, non-proliferating cells. When PARP activation was blocked, necrotic cell death failed to occur despite exposure to the chemotherapeutic agents.
Chemotherapeutic drugs activate PARP by damaging DNA. While this is effective at killing tumor cells, it comes at the price of damaging many normal cells, creating mutations that might lead to new cancers. In contrast, the new work suggests that drugs directly activating PARP might prove effective at treating cancer without many of the serious side effects of existing chemotherapy.
"Our next step is to try to safely manipulate necrotic cell death in cancerous tumors, " said Wei-Xing Zong, PhD, study author and Post-Doctoral Fellow at the AFCRI. "Ultimately, the hope is that this could lead to new, safer targeted therapies to kill cancer cells before they turn into deadly tumors that can spread elsewhere in the body."
Funding for the study, which began in January 2003 and finished in December, was provided through research grants from the AFCRI, Cancer Research Institute (CRI), and the Leukemia and Lymphoma Society of America.
Editor's Note: You may also find this news release on-line at www.uphs.upenn.edu/news
About the Abramson Cancer Center:
The Abramson Cancer Center of the University of Pennsylvania was established in 1973 as a center of excellence in cancer research, patient care, education and outreach. Today, the Abramson Cancer Center ranks as one of the nation's best in cancer care, according to US News and World Report, and is one of the top five in National Cancer Institute (NCI) funding. It is one of only 39 NCI-designated comprehensive cancer centers in the United States. Home to one of the largest clinical and research programs in the world, the Abramson Cancer Center of the University of Pennsylvania has 275 active cancer researchers and 250 Penn physicians involved in cancer prevention, diagnosis and treatment. More information about the Abramson Cancer Center is available at: www.pennhealth.com/cancer
Genes & Development