 | Craig Crews, pictured in his laboratory with first-year graduate student Erin Betters, recently won an Alexander von Humboldt Foundation Research Fellowship for his work in chemical biology. |
A Yale scientist is uncovering how small molecule components of traditional herbals and other unusual therapies work. In the process, he is finding the keys to treating diseases from rheumatoid arthritis to cancer, and answering some basic issues in developmental biology, according to reports published this year in the journal Chemistry & Biology.
Craig Crews, associate professor in molecular, cellular and developmental biology (MCDB), and chemistry and pharmacology, identified the mechanisms by which the biologically active component of a traditional Chinese herbal therapy, lei gong teng, works.
The plant extract contains triptolide, an active anti-inflammatory small molecule. It has multiple biological activities, including anti-tumor, anti-fertility and immunosuppressive effects.
Triptolide has therapeutic potential because it can work together with and enhance the effect of anti-cancer agents, and it is currently in clinical trials as a treatment for prostate cancer. Crews' research team also has determined that it can be used as a treatment for inflammatory disorders such as rheumatoid arthritis.
"We focused on the binding activity of triptolide and triptolide-like molecules in cells to see whether the various physiological effects have a common mechanism and/or interact with a common protein target," says Crews. "We discovered a link to calcium dependence."
The researchers' results show that while triptolide alters at least two distinct cellular pathways -- transcription and programmed cell death -- the pathways require different concentrations of both calcium and triptolide, dictating the two different biological outcomes. This understanding is a key to the use of triptolide and similar derivative compounds, and a blueprint for the possible design of new active drug compounds.
Crews and his team also applied their "mode of action" work with another small molecule inhibitor. Fumigillin is a natural extract from the fungus Aspergillus fumigatus and is known to be a potent inhibitor of blood vessel formation. It has been isolated and a drug based on its structure, TNP-470, is now in clinical trials for treatment of Kaposi's sarcoma, renal cell, breast and other cancers. Crews previously used a chemical genetic approach and determined that the enzyme protein targeted by this compound is MetAP-2 (methionine aminopeptidase-2).
Although the MetAP-2 target was identified, the cellular signaling pathway that was blocked by fumigillin was unknown. The Crews lab -- in collaboration with Scott Holley, assistant professor of MCDB -- studied this question by using morpholino oligonucleotides to selectively "knock down" the activity of MetAP-2 in the early development of zebrafish, a useful model for studying vertebrates.
They have recently reported the reason that blocking this target alters the outgrowth of blood vessels into tumors. "Our findings shed light on a question of basic developmental biology and offer insight into the next generation of targeted anti-tumor therapies," says Crews.
An important aspect of blood vessel growth into tumors, is just that -- they grow into tumors, notes Crews. He found that the MetAP-2 target controls the directionality of the vessel growth. Specifically, it blocks directional growth in the planar cell polarity pathway, a developmental control that was first characterized in fruit flies. The pathway was shown to act specifically during development, cell differentiation and tumor formation. Flies with defects in this pathway had bristles randomly oriented, rather than pointing in one direction.
Crews says that treatment of cancer with this "anti-angiogenic" agent targets only this new directed growth, rather than the stabilizing growth and healing that is a normal part of ongoing blood vessel repair in the body.
Now that the roles of triptolide and calcium, and fumigillin and MetAP-2 are known, Crews and his team are focusing on design of potential therapies that target these pathways.
This year Crews was awarded an Alexander von Humboldt Foundation Research Fellowship as an international leader in the field of chemical biology. His work was cited for exceptional relevance at the interface of chemistry and biology embracing analysis of the biological activity of natural products, the total synthesis of natural products and far-reaching investigations in chemical genetics.
-- By Janet Rettig Emanuel
T H I S
Scientist's molecular research
yields clues about herbal therapies
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