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 New malaria analysis method reveals disease severity in minutes
14.08.2017 | University of British Columbia

nachricht New type of blood cells work as indicators of autoimmunity
14.08.2017 | Instituto de Medicina Molecular

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: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>