Novel Antimicrotubule Agents for Breast Cancer

摘要

Stathmin is a microtubule destabilizing protein that interacts with two tubulin heterodimers to form a ternary stathmin-tubulin complex. This interaction is critical for the dynamic regulation of interphase & mitotic microtubules. Here, we asked whether intracellular delivery of stathmin-like fusion peptide(s) could prevent the normal association of stathmin with tubulin and mediate an anti-proliferative effect in in vitro models of human breast cancer. Evaluation of intracellular uptake of the peptide(s) demonstrated that breast cancer cells could effectively take up the designed peptides. Proliferation assays showed significant growth inhibitory effects in breast cancer cells exposed to wild type or mutant peptides compared to cells exposed to a control peptide. Furthermore, immunofluorescence analysis of breast cancer cells exposed to the designed peptides showed marked inhibition of microtubule polymerization. This suggests that the observed antiproliferative effect is likely a result of inhibition of microtubule assembly. Our current studies are aimed towards evaluating the biologic effects of the fusion peptide(s) in the absence & presence of vinblastine to determine if the fusion peptide(s) interact synergistically with vinblastine in breast cancer cells. These studies should provide the proof-of-principle that peptide(s) could be used to modulate stathmin function and inhibit malignant proliferation of breast cancer cells.