Title:From Natural Products to Designer Drugs: Development and Molecular Mechanisms Action of Novel Anti-Microtubule Breast Cancer Therapeutics
Volume: 17
Issue: 22
Author(s): Tejashree Mahaddalkar and Manu Lopus*
Affiliation:
- Experimental Cancer Therapeutics and Chemical Biology, UM-DAE Centre for Excellence in Basic Sciences, Kalina, Mumbai,India
Keywords:
Microtubule-targeted drugs (MTDs), Maytansine, Trastuzumab, Ixabepilone, Semisynthetic.
Abstract: Microtubule-targeted drugs (MTDs) have been on the forefront of breast cancer chemotherapy.
Classic MTDs, such as paclitaxel and their semisynthetic derivatives, have achieved considerable
success in the clinical management of breast neoplasms. In order to improve the specificity and to reduce
undesirable, dose-limiting toxicities of these drugs, a plethora of novel compounds are being synthesized
and investigated in laboratories worldwide. Due to their crucial roles during cell division, and
to the fact that the suppression of their innate ‘dynamic instability’ can arrest cell cycle progression, microtubules
formed an attractive target for cancer chemotherapy. Kadcyla (ado-trastuzumab emtansine),
Halaven (eribulin mesylate), and Ixempra (Ixabepilone) are three relatively-novel, microtubule-targeting
antibreast cancer drugs. Kadcyla was developed by conjugating a very potent derivative of the natural
product maytansine to trastuzumab, a HER2-targeted monoclonal antibody. Kadcyla is a double-edged
weapon, that is, it prevents receptor dimerization to inhibit cell proliferation, and then it enters inside the
target tumour cell by receptor-mediated endocytosis and ensures death of the cell. Halaven (eribulin mesylate),
created by simplifying the structure of the marine sponge-derived molecule Halichondrin B,
works primarily by suppressing the growth rates of microtubules and thereby inducing cell cycle arrest
and cell death. Ixabepilone, the semisynthetic analogue of epothilone B, suppresses the shortening rates
of dynamic microtubules resulting in cell cycle inhibition and cell death. In order to improve the efficacy
and reduce drug-induced side effects, novel therapeutic strategies, including liposome-mediated
drug delivery, are being investigated.
