Development of Novel Noscapinoids Mode of Action and Experimental Evaluation as Potent Anticancer Compound

Abstract

Microtubules are major cytoskeletal structures responsible for maintaining genetic stability during cell division. The dynamics of these polymers is crucial for this function, which can be described as their growth rate at the plus ends, catastrophic shortening, frequency of transition between two phases, pause between two phases, and their release from the microtubule-organizing center and treadmilling. Microtubule lattice also tracks the axonal transport of organelles driven by anterograde and retrograde molecular motors to generate and maintain axonal integrity. Interference with microtubule dynamics often leads to programmed cell death and hence the microtubule-binding drugs are currently used to treat various malignancies. Although useful, the currently used microtubule drugs such as vincas and taxanes are limited due to the emergence of drug resistance. There have been multiple mechanisms for antimicrotubule drug resistance including overexpression of the drug-efflux pumps, misexpression of tubulin isotypes and perhaps mutational lesions in tubulin itself. However, the pharmacological profile of microtubule-binding agents has not been ideal. Most of tubulin binding drugs need to be infused over long periods in the clinic because they are not water soluble and cause hypersensitive reactions due to the vehicle solution. Furthermore, the normally dividing cells within the healthy tissues such as intestinal crypts, hair follicles, and bone marrow are also vulnerable to these agents leading to toxicities. In addition, the nerve cells dependent on molecular traffic over long distances undergo degenerative changes causing peripheral neuropathies. newline