Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists find second way to kill cancer cells: Discovery opens possibilities for new therapies

14.05.2004


New study shows aklylating DNA damage stimulates regulated necrotic cell death



Researchers at the Leonard and Madlyn Abramson Family Cancer Research Institute at the University of Pennsylvania have found a second way by which chemotherapeutic agents can kill cancer cells. The finding – which will appear online and ahead of print in the June 1st edition of the journal Genes & Development – represents an important advance in understanding how and why some cancer cells die and others do not in response to existing chemotherapy. The results suggest the possibility that targeted therapies can be developed which will force cancer cells to die before they can grow into tumors.

"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.

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

David March | EurekAlert!
Further information:
http://www.pennhealth.com/cancer
http://www.uphs.upenn.edu/news/

More articles from Health and Medicine:

nachricht Tracking movement of immune cells identifies key first steps in inflammatory arthritis
23.01.2017 | Massachusetts General Hospital

nachricht Team discovers how bacteria exploit a chink in the body's armor
20.01.2017 | University of Illinois at Urbana-Champaign

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Quantum optical sensor for the first time tested in space – with a laser system from Berlin

For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.

According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Arctic melt ponds form when meltwater clogs ice pores

24.01.2017 | Earth Sciences

Synthetic nanoparticles achieve the complexity of protein molecules

24.01.2017 | Life Sciences

PPPL physicist uncovers clues to mechanism behind magnetic reconnection

24.01.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>