Macroketone Blocks Metastasis in Mouse Model

Cancer researchers have synthesized a potent analogue of a naturally occurring compound that prevents most tumor metastasis in a mouse model.

Investigators at Weill Cornell Medical College (New York, NY, USA) have been working for several years with migrastatin, a natural product secreted by Streptomyces bacteria. While migrastatin has only weak antimetastasis activity, synthetic analogues of this compound such as macroketone are much more effective inhibitors of tumor cell migration, invasion, and metastasis.

Results published in the April 15, 2010, online edition of the journal Nature revealed that mice implanted with tumor cells and then treated with macroketone did not die of metastatic cancer, while untreated animals did. In experiments where animals were treated a week following tumor transplantation, 80% of the treated animals survived.

Macroketone did not prevent implanted cancer cells from forming tumors or from growing, but it did stop tumor cells from spreading. This was true even when macroketone was given after tumors had already formed. At the molecular level, the action of macroketone was shown to be through its specific binding to the actin-binding site on the cytoskeleton protein fascin. This binding disrupted the mechanism used by the cancer cells to move.

"This suggests to us that an agent like macroketone could be used to both prevent cancer spread and to treat it as well,” said senior author Dr. Xin-Yun Huang, professor of physiology and biophysics at Weill Cornell Medical College. "Of course, because it has no effect on the growth of a primary tumor, such a drug would have to be combined with other anticancer therapies acting on tumor cell growth. The beauty of this approach is that fascin is overexpressed in metastatic tumor cells but is only expressed at a very low level in normal epithelial cells, so a treatment that attacks fascin will have comparatively little effect on normal cells -- unlike traditional chemotherapy which attacks all dividing cells.”

"More than 90% of cancer patients die because their cancer has spread, so we desperately need a way to stop this metastasis,” said Dr. Huang. "This study offers a paradigm shift in thinking and, potentially, a new direction in treatment.”

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