Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Exploiting the stress response to detonate mitochondria in cancer cells

Researchers at The Wistar Institute have found a new way to force cancer cells to self-destruct. Low doses of one anti-cancer drug currently in development, called Gamitrinib, sensitize tumor cells to a second drug, called TRAIL, also currently in clinical development as part of an anticancer regimen.

Their findings, published in the April issue of the Journal for Clinical Investigation, show how this combination approach kills tumor cells in both mouse models of glioblastoma and human glioblastoma cells. Glioblastomas are the most common and aggressive form of malignant brain cancer, affecting roughly 6 out of every 100,000 people. There is currently no effective treatment for glioblastoma, and patients rarely survive more than a year after diagnosis.

"We found that a low dose of Gamitrinib makes cancer cells susceptible to TRAIL, bypassing many of the mechanisms tumors use to survive," said senior author Dario Altieri, M.D., the Robert and Penny Fox Distinguished Professor at Wistar and director of The Wistar Institute Cancer Center. "Here we have found a new way to combine cancer therapies, one that could be applied to treating many types of cancer because both of these drugs target different mechanisms of tumor cell survival that revolve around mitochondria."

As commonly depicted in high school biology texts, mitochondria are the "powerhouses" of the cells, organelles whose main function is to turn sugar into useable energy. What is less commonly known is the role of mitochondria in programmed cell death, or apoptosis, the self-destruct system hardwired into every cell. Apoptosis evolved, in part, as a way for the body to react to extreme stress, a means to sacrifice damaged cells for the greater good of the organism. Cancer cells rely on the mitochondria to provide the energy rapidly-growing tumors need to survive, but find ways to block the signaling pathways that trigger apoptosis. Many researchers, including Altieri, have looked for ways to force tumor cells to hit this self-destruct switch.

Gamitrinib is a chemical inhibitor first developed by Altieri and his colleagues in 2009 at the University of Massachusetts. The drug binds to and inhibits Hsp90—Heat Shock Protein-90—a so-called chaperone protein that is highly active in mitochondria and other cellular organelles where it helps regulate and "rescue" other proteins, particularly in times of stress. Their previous studies have shown that Gamitrinib is effective in damaging tumor cell mitochondria, which can lead to cell death.

"When tumor cells are confronted with lower concentrations of Gamitrinib, they mount a stress-related defensive system, essentially eating damaged mitochondria and altering how genes are turned on and off to compensate for induced defects in the mitochondria," Altieri said. "This process naturally suppresses Nuclear Factor-kappa Beta, a protein that prevents apoptosis from happening. Ironically, it's this very defensive measure that we can exploit in killing tumor cells."

Nuclear Factor-kappa Beta (NF-êÂ) broadly promotes survival in tumors by halting the processes that lead to apoptosis. Altieri and his colleagues wanted to see if the suppression of NF-ê would provide an opportunity for TRAIL, a small engineered molecule that mimics the signals used to induce apoptosis.

In their experiments, researchers confirmed previous studies that showed how TRAIL alone did not affect glioblastoma in cell and animal models of the disease. TRAIL plus Gamitrinib, however, stimulated damage to mitochondria in tumor cells, which started a cascading series of reactions, culminating in cell death. Preclinical experiments conducted in mouse models of glioblastoma demonstrated that the combination did not cause any detectable toxic side effects.

According to Altieri, the fact that Gamitrinib and TRAIL are in clinical development already may help speed the process that could see eventual clinical trials of the two drugs together. "There is much preclinical work to be done, of course, but we are very interested in laying the groundwork now toward initial clinical trials," said Altieri.

Going forward, the researchers also plan to delve deeper into the cellular processes at work.

"I find the basic biology of this system fascinating, since here we show how mitochondria, which are the only organelles that have their own DNA, must communicate with the DNA in the cell's nucleus," Altieri said. "It is not a well-understood process by any means."

This study was supported by grants from the National Institutes of Health to Altieri, and a grant to co-author Markus D. Siegelin, M.D. from Deutsche Forschungsgemeinschaft (German Research Foundation).

The co-first authors of the study are Takehiko Dohi, Ph.D., currently a member of the Altieri lab at Wistar, and Siegelin, formerly a member of Altieri's previous laboratory at the University of Massachusetts Medical School and now a resident clinician at Columbia University. Contributors from the University of Massachusetts also include Christopher M. Raskett, Gregory M. Orlowski, Christine M. Powers, Candace A. Gilbert, Alonzo H. Ross, and Janet Plescia.

Greg Lester | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>