How do Microtubule Drugs act as Medicines

Date: Friday, 3 February 2023

Time: 2.00PM – 3.00PM

Host: Prof Hong Wanjin

Microtubules are dynamic protein fibers that transport vesicles in non-dividing cells and chromosomes during mitosis. Small molecule drugs that target microtubule polymerization dynamics, many of them derived from plant toxins, are important medicines. We know how they work at the molecular level, but not how they act therapeutically in the human body. Taxanes stabilize microtubules and are used to treat adult solid cancers. They block mitosis in cancer cells, but so do more recent drug candidates that failed in the clinic, so taxanes must have additional actions. We found that taxanes, alone among anti-mitotics tested in the clinic, promote chromatin bridge formation which triggers interferon secretion. This immune activating signal may contribute to tumor regression. The ancient drug colchicine destabilizes microtubules and is used at low doses to treat gout and other inflammatory diseases. Using mice to model PK-PD and therapeutic mechanism, we found that colchicine acts selectively in the liver to trigger release of anti-inflammatory hepatokines which include a non-canonical form of GDF15. These act on circulating myeloid cells to inhibit inflammation. Our unexpected findings that both taxanes and colchicine modulate inflammatory signaling illustrates the importance of inflammatory pathways in disease and therapy and has implications for drug discovery. Our work also highlights the importance of uneven tissue distribution in selective action of natural product drugs. 

Dr. Mitchison is interested in all aspects relating to microtubules, the cytoskeleton, and cell division. Dr. Mitchison received his Ph.D. in Biochemistry and Biophysics from the University of California, San Francisco. During his PhD work at the University of California, San Francisco with Dr. Marc Kirschner, he discovered dynamic Instability of microtubules, a fundamental aspect of cytoskeleton biology and since then has studied the biochemistry, dynamics and spatial organization of microtubules and actin filaments with a focus on cell division mechanisms. Much of his lab's work in this area is based on live fluorescence imaging and has been at the forefront of the application of novel optical methodologies to living cells. In 1997 he moved to Harvard Medical School to Co-direct the Institute of Chemistry and Cell Biology, a collaboration between chemists and cell biologists, to develop and apply small molecule screening capabilities in academia. As part of this effort, Dr. Mitchison's developed a strong interest in cancer chemotherapy and in more rational approaches to drug development in general. In 2004 he co-founded a new department, Systems Biology, that aims to bring systematic and quantitative methods to bear on problems in basic cell biology and medicine and in 2011 he helped found the Systems Pharmacology initiative at Harvard Medical School, a major interest area within the department, co-Directed by Peter Sorger and himself. Dr. Mitchison is the Hasib Sabbagh Professor of Systems Biology, and co-Director of the Initiative in Systems Pharmacology at Harvard Medical School.

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