Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


The good and bad side of anti-cancer compounds

Compounds known as “HDAC inhibitors” exhibit cancer-killing activities in cultured cells. While they are currently being tested as anti-cancer agents in clinical trials, just how they execute their effects is unclear.

In a pair of recent papers, Vanderbilt-Ingram Cancer Center investigators provide a potential mechanism by which HDAC inhibitors specifically damage cancer cells and offer clues about possible adverse effects of these compounds – findings with important implications for their clinical use as cancer therapies.

Scott Hiebert, Ph.D., professor of Biochemistry and Medicine, and colleagues initially set out to study how chromosomal translocations – which happen when chromosomes break and rejoin, creating new genes at the breakpoints – cause acute leukemias.

He previously had found that a chromosomal translocation common in acute myeloid leukemias led to the formation of a new protein, a mutant transcription factor, that actively turned genes off. Enzymes known as histone deacetylases (HDACs) helped the mutant protein turn genes off by stabilizing the tightly coiled structure of DNA in chromosomes, making it inaccessible to proteins that transcribe DNA.

“We thought that if we could inhibit these HDACs, we could turn the genes back on and cure leukemia,” Hiebert explained.

While there are at least 17 different HDACs, Hiebert’s work suggested that one in particular, called HDAC3, might be the critical HDAC in triggering acute leukemia.

To investigate the effects of inhibiting HDAC3, Hiebert and colleagues genetically engineered mice lacking the protein. However, the mice died before birth. Even when grown in cell culture, mouse cells lacking HDAC3 died.

“The question is: why are they dying? And what we found was kind of surprising,” he said.

In the April 11 issue of Molecular Cell, Hiebert and colleagues report that these cells die because they can’t repair the DNA damage that occurs naturally when the cells copy their DNA during cell division. HDAC3 inhibition only killed cells that were in the process of DNA replication. However, cells cultured in a medium that stalled cell division – a situation similar to the mature cells in most adult tissues – survived.

This provided an important clue as to why HDAC inhibitors specifically kill tumor cells – which divide rapidly and prolifically – and spare healthy cells.

“If we take cells out of the cycle, making them quiescent, like most of your tissue cells are, they aren’t affected by (HDAC inhibitors) or by the (genetic) inactivation of HDAC3. Whereas cells that are actively cycling or dividing, like the tumor cell, are susceptible,” said Hiebert.

“We think that these HDAC inhibitors are actually having a therapeutic benefit against cancer by causing DNA damage…and we’re not repairing that damage. That eventually leads the cell to die,” he explained.

Although previous studies suggest that HDAC inhibitors have some tumor-killing ability on their own, Hiebert’s recent findings especially support using HDAC inhibitors as adjuncts to chemotherapy or radiation treatment, both of which induce DNA damage. Giving an HDAC inhibitor beforehand may prevent tumor cells from being able to repair the DNA damage that will be inflicted by the radiation or chemotherapy treatments.

“We’re excited about that because that’s where the real benefit of these drugs will eventually come in,” he says.

HDAC inhibition isn’t without side effects, however. And another recent paper from Hiebert’s lab, published in the EMBO Journal in March, provides some insight into how HDAC inhibition might cause liver damage.

In that study, Hiebert’s group turned off HDAC3 in the liver only. These mice, which did survive to adulthood, developed extensive liver damage with grossly enlarged and fatty livers. The mice also had major metabolic abnormalities, reflected in elevated cholesterol and triglyceride levels.

Fortunately, the HDAC inhibitors currently under investigation are short-lived in the body, which may limit any potential adverse effects.

“I think the short half-life in people is actually going to be a benefit for these compounds, because they are transient therapies,” he noted.

Hiebert’s lab is following these mice to determine the long-term effects of HDAC inhibition. And, because the available HDAC inhibitors are relatively broad-spectrum, inhibiting several of the 17 HDACs, he is looking to develop HDAC inhibitors that more selectively target HDAC3.

The Food and Drug Administration recently approved an HDAC inhibitor called SAHA (suberoylanilide hydroxamic acid) for treating a form of T-cell lymphoma – which means that the drug will likely be given off-label for other types of tumors.

While this marks a major step forward in the therapeutic use of HDAC inhibitors, Hiebert notes, “we think they can be used better. And that’s why we’re excited by these results.”

Dagny Stuart McMillin | EurekAlert!
Further information:

More articles from Studies and Analyses:

nachricht Diagnoses: When Are Several Opinions Better Than One?
19.07.2016 | Max-Planck-Institut für Bildungsforschung

nachricht High in calories and low in nutrients when adolescents share pictures of food online
07.04.2016 | University of Gothenburg

All articles from Studies and Analyses >>>

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 >>>