Session Speaker

Beautiful Foliage of Meadow Saffron (Genus-Colchicum) with White-Pink-to Purple Six-Parted Blooms Toxic to Animals
H.C. Joshi

Beautiful foliage of meadow saffron (genus-Colchicum) with white-pink-to purple six-parted blooms was toxic to animals that ate it. Chemists then isolated the toxic compound, colchicine, from the corms and seeds of this plant and its high affinity cellular receptor, tubulin, turned out to be the abundant protein that assembles into cellular microtubules (MTs). MTs make many cellular machineries, the most notable one is the MT spindle responsible for the maintenance of chromosome segregation fidelity during cell division. (Another such example of plant-derived compounds is podophyllotoxin). Both poisons disassemble these cellular machines causing havoc in the life of a cell. Thus, a small molecule resulted in the fundamental understanding of several vital cellular processes including the transport of chromosomes and many intracellular organelles. They are also involved in maintaining the structural integrity of many organelles such as the golgi, endoplasmic reticulum and mitochondria. Using a chemical-genetic approach, we have screened structurally similar compounds of common structural themes (mutant molecules) in pursuit of finding chemicals that can alter only subtle MT-behaviors (e.g., polymerization/depolymerization dynamics). The hope was to find small molecular tools to study nuances of mitosis in normal progression of healthy and cancer cells through mitosis. Our screens lead to an opium derived non-narcotic molecule, noscapine that binds tubulin and mitigates MT-dynamics enough to activate cell cycle checkpoints that halt progression of cell cycle in normal cells. Owing to the various mutations in the genome of cancer cells, their weak checkpoint mechanisms result in gain or loss of many chromosomes and undergo self-destructive apoptosis upon treatment with noscapine. Normal healthy cells can remain arrested in mitosis for long periods of time—long enough for the drug to be metabolized and excreted from animal and human bodies. Thus noscapine and its further rationally designed derivatives (collectively called, noscapinoids) show significant regression of a various cancers in preclinical animal experiments. There are orally available non-toxic drugs with favorable pharmacokinetics that has now shown promising results in Phase I/II clinical trials. We discuss the progress and future prospects of this line of research in novel chemotherapeutic intervention of disease.