The research team has provided a potential mechanism by which HDAC inhibitors particularly damage cancer cells and offer clues about possible adverse effects of these compounds.
The team says that the findings have important implications for HDAC inhibitors' clinical use as cancer therapies.
In fact, the researchers have previously proved that HDAC inhibitors may have its side-affects like liver-damage.
The researchers led by Scott Hiebert, Ph.D., professor of Biochemistry and Medicine, earlier 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.
Out of the 17 different HDACs, the researchers specifically pointed to one, called HDAC3, which may be the critical HDAC in triggering acute leukemia. For their investigation, they genetically engineered mice lacking HDAC3, but the mice died before birth. In fact, mice grown in cell culture without HDAC3, met the same fate.
They died because they were unable to repair the DNA damage that occurs naturally when the cells copy their DNA during cell division. HDAC inhibitors specifically kill tumour 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 tumour cell, are susceptible. 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," said Hiebert.
Hiebert said that giving an HDAC inhibitor beforehand might prevent tumour 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 said.
However, HDAC inhibition has its side-effects as well; in fact, it has been proved in a previous research that HDAC inhibition might cause liver damage. However, the good news is that 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.
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 tumours.
The study is published in the recent issue of Molecular Cell.