Washington, May 9 (ANI): Researchers including one of Indian origin have come up with a potent new drug that clogs up the recycling machinery and kills tumour cells in mouse models.
All cells have the capability to recycle unwanted or damaged proteins and reuse the building blocks as food.
But cancer cells have ramped up the system, called autophagy, and rely on it to escape damage in the face of chemotherapy and other treatments.
Ravi K. Amaravadi, MD, assistant professor of Medicine, and colleagues showed previously that an old malaria drug, hydroxychloroquine, reduces autophagy in cancer cells and makes them more likely to die when exposed to chemotherapy.
The strategy is currently being tested in clinical trials, and preliminary results are promising. The catch, though, is that it's not always possible to give patients a high enough dose of hydroxychloroquine to have an effect on their tumour cells.
Amaravadi teamed up with Jeffrey Winkler, PhD, the Merriam Professor of Chemistry, to design a series of more potent versions of chloroquine.
They describe the design, chemical synthesis, and biological evaluation of a highly effective, new compound called Lys05, in the early edition of the Proceedings of the National Academy of Sciences this week.
Unlike hydroxychloroquine, which has little impact on tumour cells when used as a single agent, the new drug, called Lys05, slows tumour growth in animal models even in the absence of other anti-tumour therapies.
What's more, the Lys05 dose that is toxic to cancer cells, which are addicted to recycling and rely on it much more heavily than healthy cells, has little or no effect on healthy cells.
"We see that Lys05 has anti-tumour activity at doses that are non-toxic for the animals," Amaravadi said.
"This single-agent anti-tumour activity suggests this drug, or its derivative, may be even more effective in patients than hydroxychloroquine," Amaravadi added.
Remarkably, however, when the investigators increase the dose of Lys05, some animals develop symptoms that mimic a known genetic deficiency in an autophagy gene, ATG16L1, which affects some patients with Crohn's disease.
That similarity - technically called a phenocopy - clearly shows that Lys05 works by interfering with the recycling system in cells.
Lys05, and its companion compound Lys01, aren't quite ready for testing in patients, according to Amaravadi. Before that can happen, the molecules need to be optimized and undergo more toxicity testing in animals. Amaravadi and Winkler hope to team up with an industry partner for that portion of the project.
In the meantime, though, Amaravadi said that the work illustrates just how important autophagy is to cancer cells, and provides an important new step for future therapies. (ANI)
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