Block its recycling system, and cancer kicks the can: study

May 8, 2012

All cells have the ability 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. Now, researchers at the Perelman School of Medicine; the Abramson Cancer Center; and the School of Arts and Sciences, at the University of Pennsylvania, have developed a potent new drug that clogs up the recycling machinery and kills tumor cells in mouse models.

Ravi K. Amaravadi, MD, assistant professor of Medicine, and colleagues showed previously that an old , , 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 tumor 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, , and biological evaluation of a highly effective, new compound called Lys05, in the early edition of the this week.

Unlike hydroxychloroquine, which has little impact on when used as a single agent, the new drug, called Lys05, slows tumor growth in animal models even in the absence of other anti-tumor 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-tumor activity at doses that are non-toxic for the animals," Amaravadi says. "This single-agent anti-tumor activity suggests this drug, or its derivative, may be even more effective in patients than hydroxychloroquine." 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 says the work illustrates just how important autophagy is to , and provides an important new step for future therapies.

Explore further: Cell recycling protects tumor cells from anti-cancer therapy

Related Stories

Cell recycling protects tumor cells from anti-cancer therapy

March 6, 2008

Cells have their own recycling system: Discarded cellular components, from individual proteins through to whole cellular organs, are degraded and the building blocks re-used in a different place. The scientific term for this ...

Small molecules can starve cancer cells

October 9, 2011

All cells in our body have a system that can handle cellular waste and release building blocks for recycling. The underlying mechanism is called autophagy and literally means "self-eating". Many cancer cells have increased ...

Cancer's sweet tooth may be its weak link

November 16, 2011

Researchers at Albert Einstein College of Medicine of Yeshiva University have discovered that cancer cells tap into a natural recycling system to obtain the energy they need to keep dividing. In a study with potential implications ...

Recommended for you

Oxygen can impair cancer immunotherapy in mice

August 25, 2016

Researchers have identified a mechanism in mice by which anticancer immune responses are inhibited within the lungs, a common site of metastasis for many cancers. This mechanism involves oxygen inhibition of the anticancer ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.