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Enzyme Inhibitor Helps Tissue Heal In Mice

Drug Discovery: Small molecule blocks the breakdown of key prostaglandin to promote cell proliferation

by Stu Borman
June 11, 2015 | A version of this story appeared in Volume 93, Issue 24

A newly identified small molecule increases the rate of tissue regeneration in the colon, liver, and bone marrow of mice. With further testing and development, such a compound could lead to therapies that would help patients heal tissues damaged by disease or excised through surgery.

In previous studies on animals or patients, scientists have tried to accelerate tissue and blood cell growth by administering analogs of prostaglandin E2 (PGE2), a lipid that promotes regeneration by initiating signals that cause stem cells to proliferate. They’ve also administered agents that stimulate PGE2 signaling and treated stem cells with PGE2 analogs before injecting them into patients. But none of this work has yet led to approved tissue regeneration therapies.

The new strategy boosts levels of PGE2 through another mechanism: by inhibiting an enzyme that breaks it down. The approach was devised by Sanford D. Markowitz and Stanton L. Gerson of Case Western Reserve University; Joseph M. Ready, Bruce Posner, and James K. V. Willson of the University of Texas Southwestern Medical Center, Dallas; and coworkers (Science 2015, DOI: 10.1126/science.aaa2340).

The team used high-throughput screening to find SW033291, a small molecule that inhibits a key prostaglandin-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase. Administering the agent to mice doubled levels of PGE2 in their bodies, doubled rates of tissue regeneration in their colons and livers, and made bone marrow reconstitution faster. The researchers next plan to test an easier-to-administer version of the molecule for toxicity in animals and, if that compound appears safe, they hope to apply to the Food & Drug Administration to start testing it in people, Markowitz says.

Colorectal cancer expert Raymond DuBois of Arizona State University notes that previous work has linked elevated PGE2 levels to cancer, so “very careful safety studies will need to be completed before this approach can be used in humans.”

Hematologist Leonard I. Zon of Harvard Medical School, whose group played a leading part in discovering PGE2’s natural role in tissue regeneration, comments that when prostaglandins are given to patients directly, they can degrade quickly in the bloodstream, diminishing the effectiveness of the therapy. An advantage of the new approach is that it sidesteps that problem by actively preventing breakdown, Zon says.



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