Scientists based in the U.S. at the University of California Davis, and in Taiwan at Taipei Medical University as well as the National Health Research Institutes have simultaneously discovered a new process of “chromatophagy” cellular suicide and shed light on the way a “starvation” drug deprives cancer cells of arginine, a necessary amino acid.
A number of Phase I, II and III clinical trials are testing the compound for use either alone or in combination with other drugs. These trials can be accessed here: Clinical trials involving ADI-PEG20.
Cells when stressed, whether cancerous or not, undergo a process of cellular suicide that involves controlled dismantling of its interior components such as proteins, DNA, and various compartments. By far the most famous of such processes is “apoptosis”. The authors in this study have found another, distinct process involving mitochondria dysfunction, reactive oxygen species (ROS) generation, DNA leakage, and chromatin autophagy,
The senior author, Professor Hsing-Jien Kung, both a cancer biology at UC Davis and the Director of the National Health Research Institutes in Taipei, Taiwan, first discovered in 2009 the basic mechanism by which arginine shortage kills cancer cells.
“Traditional cancer therapies involve ‘poisoning‘ by toxic chemicals or ‘burning‘ by radiation cancer cells to death, which often have side effects,” according to Professor Kung. “An emerging strategy is to ‘starve’ cancer cells to death, taking advantage of the different metabolic requirements of normal and cancer cells. This approach is generally milder, but as this study illustrates, it also utilizes a different death mechanism, which may complement the killing effects of the conventional therapy.”
The 2009 discovery spurred the development of a therapeutic that is now at various stages in several clinical trials, for treatment of cancers as diverse as melanoma, prostate, liver, sarcoma and other cancers that themselves lack an arginine synthesis enzyme known as argininosuccinate synthetaseand therefore must rely on external sources to stay alive.
The newly released study describes a novel process in which arginine starvation cause mitochondrial dysfunction, release of ROS, damage and leakage of DNA from the nucleus, and subsequent consumption of the leaked DNA which they call chromatophagy. The cells cannot survive without DNA. The scientists tested the hypothesis more deeply by showing that application of an ROS scavenger molecule to the cells is able to weaken the chromatophagy outcome.
The more commonly known path to cellular suicide is known as apoptosis. The immune system under normal circumstances is able to force a suicide when something is recognized to be “unnatural” about the cell, such as when it goes cancerous or is infected by an agent. Unsurprisingly, mutations arise that enable cancer cells to survive such death signals.
“It has long been recognized that some cancer cells are resistant to apoptosis,” said co-author Professor Richard Bold, professor at the UC Davis Comprehensive Cancer “Now, we have another way to induce cells to undergo death that overcomes resistance to traditional apoptosis associated with cancer.”
One ancillary benefit the authors suggest is that arginine-deprivation therapy might spare patients the toxicity associated with traditional chemotherapy.
The drug is developed by Polaris Pharmaceuticals, a startup in San Diego. ADI-PEG20 is a catalytic enzyme that breaks down arginine into simpler molecules. The therapeutic drug is in phase III clinical trials for liver cancer, phase II for melanoma and phase I for prostate cancer.
The research was published on July 25th, 2014 in Proceedings of the Academy of Sciences