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 Inhaling air pollution-like irritant alters defensive heart-lung reflex for hypertension
19.06.2019 | University of South Florida (USF Innovation)

nachricht Nitric oxide-scavenging hydrogel developed for rheumatoid arthritis treatment
06.06.2019 | Pohang University of Science & Technology (POSTECH)

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: Successfully Tested in Praxis: Bidirectional Sensor Technology Optimizes Laser Material Deposition

The quality of additively manufactured components depends not only on the manufacturing process, but also on the inline process control. The process control ensures a reliable coating process because it detects deviations from the target geometry immediately. At LASER World of PHOTONICS 2019, the Fraunhofer Institute for Laser Technology ILT will be demonstrating how well bi-directional sensor technology can already be used for Laser Material Deposition (LMD) in combination with commercial optics at booth A2.431.

Fraunhofer ILT has been developing optical sensor technology specifically for production measurement technology for around 10 years. In particular, its »bd-1«...

Im Focus: The hidden structure of the periodic system

The well-known representation of chemical elements is just one example of how objects can be arranged and classified

The periodic table of elements that most chemistry books depict is only one special case. This tabular overview of the chemical elements, which goes back to...

Im Focus: MPSD team discovers light-induced ferroelectricity in strontium titanate

Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.

Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...

Im Focus: Determining the Earth’s gravity field more accurately than ever before

Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.

The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...

Im Focus: Tube anemone has the largest animal mitochondrial genome ever sequenced

Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.

The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

 
Latest News

A new force for optical tweezers awakens

19.06.2019 | Physics and Astronomy

New AI system manages road infrastructure via Google Street View

19.06.2019 | Information Technology

A new manufacturing process for aluminum alloys

19.06.2019 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>