Fermentation byproduct suppresses seizures in nerve agent poisoning

A compound found in trace amounts in alcoholic beverages is more effective at combating seizures in rats exposed to an organophosphate nerve agent than the current recommended treatment, according to new research published Read more

Post-anesthetic inertia in IH

A recent paper from neurologists Lynn Marie Trotti and Donald Bliwise, with anesthesiologist Paul Garcia, substantiates a phenomenon discussed anecdotally in the idiopathic hypersomnia (IH) community. Let’s call it “post-anesthetic inertia.” People with IH say that undergoing general anesthesia made their sleepiness or disrupted sleep-wake cycles worse, sometimes for days or weeks. This finding is intriguing because it points toward a trigger mechanism for IH. And it pushes anesthesiologists to take IH diagnoses into Read more

How much does idiopathic hypersomnia overlap with ME/CFS?

If hypersomnia and narcolepsy are represented by apples and oranges, how does ME/CFS fit Read more

head and neck cancer

Orange lichens are source for potential anticancer drug

An orange pigment found in lichens and rhubarb called parietin may have potential as an anti-cancer drug, scientists at Winship Cancer Institute of Emory University have discovered.

The results were published in Nature Cell Biology on October 19.

Caloplaca_Fenwick

Parietin, shown to have anticancer activity in the laboratory, is a dominant pigment in Caloplaca lichens. Note: this study did not assess the effects of eating lichens or rhubarb. Photo courtesy of www.aphotofungi.com

Parietin, also known as physcion, could slow the growth of and kill human leukemia cells obtained directly from patients, without obvious toxicity to human blood cells, the authors report. The pigment could also inhibit the growth of human cancer cell lines, derived from lung and head and neck tumors, when grafted into mice.

A team of researchers led by Jing Chen, PhD, discovered the properties of parietin because they were looking for inhibitors for the metabolic enzyme 6PGD (6-phosphogluconate dehydrogenase). 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. Researchers have already found 6PGD enzyme activity increased in several types of cancer cells.

“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” says Chen, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.” Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Explainer: oncolytic viruses

A recent publication from Bill Kaiser’s and Ed Mocarski’s labs in Cell Host & Microbe touches on a concept that needs explaining: oncolytic viruses.

Viruses have been subverting the machinery of healthy cells for millions of years, and many viruses tend to infect particular tissues or cell types. So they are a natural starting point for researchers to engineer oncolytic viruses, which preferentially infect and kill cancer cells.

Several oncolytic viruses have progressed to advanced clinical trials. Amgen’s “T-Vec”, a modified herpes simplex virus, could be the first to be approved by the FDA this year based on its efficacy against metastatic melanoma.  Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Fine tuning an old-school chemotherapy drug

First approved by the FDA in the 1970s, the chemotherapy drug cisplatin and its relative carboplatin remain mainstays of treatment for lung, head and neck, testicular and ovarian cancer. However, cisplatin’s use is limited by its toxicity to the kidneys, ears and sensory nerves.

Paul Doetsch’s lab at Winship Cancer Institute has made some surprising discoveries about how cisplatin kills cells. By combining cisplatin with drugs that force cells to rely more on mitochondria, it may be possible to target it more specifically to cancer cells and/or reduce its toxicity.

Cisplatin emerged from a serendipitous discovery in the 1960s by a biophysicist examining the effects of electrical current on bacterial cell division. It wasn’t the current that stopped the bacteria from dividing – it was the platinum in the electrodes. According to Siddhartha Mukherjee’s book The Emperor of All Maladies, cisplatin became known as “cisflatten” in the 1970s and 1980s because of its nausea-inducing side effects.

Cisplatin is an old-school chemotherapy drug, in the sense that it’s a DNA-damaging agent with a simple structure. It doesn’t target cancer cells in some special way, it just grabs DNA with its metallic arms and holds on, forming crosslinks between DNA strands.

But how cisplatin kills cells is more complicated. Along with the direct effects of DNA damage, cisplatin unleashes a storm of reactive oxygen species.

“We wanted to know whether the reactive oxygen species induced by cisplatin had a driving role in cell death or was more of a byproduct,” says postdoc Rossella Marullo, who is the first author of a recent paper with Doestch in PLOS One.

One possible analogy: after the 1906 San Francisco earthquake, the fires were even more destructive than the initial shaking. When asked whether to think of the reactive oxygen species production triggered by cisplatin in the same way as the fires, Doetsch and Marullo say they wouldn’t go that far.

Still, they have uncovered a critical role for mitochondria, cells’ mini-power plants, in cisplatin cell toxicity. The researchers found that mitochondria are the source of cisplatin-induced reactive oxygen species in lung cancer cells. Cancer cell lines that lack functional mitochondria* are less sensitive to cisplatin, and cisplatin’s damage to the mitochondria may be even more important than the damage to DNA in the nucleus, the authors write. However, mitochondrial damage is not important for cisplatin’s less potent [but less toxic] cousin carboplatin.

Cancer cells tend to have a warped metabolism that makes them turn off their mitochondria. This is part of the “Warburg effect” (experts in this area: Winship’s Jing Chen and Malathy Shanmugam). Cancer cells have an increased uptake of sugar, but don’t break it down completely, and use the byproducts as building materials.

What if we could force cancer cells to rely on their mitochondria again, and at the same time, by giving them cisplatin, make that painful for them? This would make cisplatin even more toxic to cancer cells in particular.

The drug DCA (dichloroacetate), which can stimulate cancer cells to use their mitochondria, can also increase the toxicity of cisplatin, at least in cancer cell lines in the laboratory, Marullo and her colleagues show.

Doetsch and radiation oncologist Jonathan Beitler are in the process of planning a clinical trial combining DCA with cisplatin for HPV (human papillomavirus)-positive head and neck cancer. The trial would test whether it might be possible to use a lower dose of cisplatin, reducing toxicity, by combining it with DCA.

“We’ve relied on cisplatin’s efficacy for decades, without fully understanding the mechanism,” Beitler says. “With this new knowledge, it may be possible to manipulate cisplatin’s action so it is more effective and less toxic.”

The applicability of cisplatin and mitochondrial tuning may depend both on cancer cell type and metabolic state, Doetsch adds.

*Cell lines that lack mitochondrial DNA can be obtained by “pickling” them in ethidium bromide, a DNA intercalation agent.

 

 

 

Posted on by Quinn Eastman in Cancer Leave a comment

Valproate: epigenetic solvent

Oncologist Johann Brandes and colleagues from Winship Cancer Institute have a recent study on the preventive effects of valproate, now prescribed for epilepsy and bipolar disorder, against head and neck cancer.

Published in Cancer, it was a clever example of number crunching, using data from the Veterans’ Administration. If you want to know about the anticancer effects of a widely used drug, check who’s already taking it for another reason (25,000 veterans were taking it). The results suggest that valproate – OR a drug that works with a similar mechanism – might be used to prevent head and neck cancer in patients who are at high risk. Also see this related paper from Brandes and colleagues on chemoprevention in lung cancer.

However, any examination of valproate should take into account neurologist Kim Meador’s work on antiepileptic drugs taken by pregnant women — he was at Emory for several years but recently moved to Stanford. His work with the NEAD study definitively showed that valproate, taken during pregnancy, increases the risk of birth defects and intellectual disability in children.

There’s even more about valproate: it might help tone-deaf adults learn to differentiate musical tones, according to one study. It has been used to enhance the reprogramming of somatic cells into induced pluripotent stem cells. It seems that valproate just shakes things up, turning on genes that have been off, erasing decisions that cells have already made.

Valproate is a tricky drug, with several modes of action: it blocks sodium channels, enhances the effects of the inhibitory neurotransmitter GABA, and inhibits histone deacetylases. Although the first two may be contributing to the antiepileptic effects, the last one may be contributing to longer-lasting changes. Histone deacetylases are a way a cell keeps genes turned off; inhibit them and you loosen things up, allowing the remodeling of chromatin and unearthing genes that were silenced.

In tumors, genes that prevent runaway growth are silenced. It may be that valproate is loosening chromatin enough to allow the growth control machinery to reemerge, although the effects observed in the Brandes paper are specific for head and neck cancer, and not other forms of cancer. The data suggest that valproate has a preventive effect with respect to smoking-related cancers and not viral-related cancers.

With adults at high risk of cancer recurrence, side effects from valproate may be more acceptable than in other situations. Even so, with follow-up research, it may be possible to isolate where the anticancer effects of valproate come from – that is, which histone deacetylase in particular is responsible – find a more specific drug, and avoid potential broad side effects.

Posted on by Quinn Eastman in Cancer, Neuro Leave a comment