Potent Small-Molecule Inhibitors Targeting Acetylated Microtubules as Anticancer Agents Against Triple-Negative Breast Cancer

Abstract

Microtubules are one of the major targets for anticancer drugs because of their role in cell proliferation and migration. However, as anticancer drugs targeting microtubules have side effects, including the death of normal cells, it is necessary to develop anticancer agents that can target microtubules by specifically acting on cancer cells only. In this study, we identified chemicals that can act as anticancer agents by specifically binding to acetylated microtubules, which are predominant in triple-negative breast cancer (TNBC). The chemical compounds disrupted acetylated microtubule lattices by interfering with microtubule access to alpha-tubulin acetyltransferase 1 (αTAT1), a major acetyltransferase of microtubules, resulting in the increased apoptotic cell death of MDA-MB-231 cells (a TNBC cell line) compared with other cells, such as MCF-10A and MCF-7, which lack microtubule acetylation. Moreover, mouse xenograft experiments showed that treatment with the chemical compounds markedly reduced tumor growth progression. Taken together, the newly identified chemical compounds can be selective for acetylated microtubules and act as potential therapeutic agents against microtubule acetylation enrichment in TNBC.

Synthesis and In Vitro Anticancer Activities of New 1,4‐Disubstituted‐1,2,3‐triazoles Derivatives through Click Approach

“…[10] Thus, these limitations compelled us to search for novel anticancer agents with high potency, less toxicity in normal cells, and an exclusive target of the action. [11,12] Herein, we report the synthesis and biological evaluation of 1,2,3-triazoles with different azide derivatives as potential anticancer agents. [13] Azoles are one of the important classes of five-membered nitrogen-containing heterocycles.…”

Microtubule Acetylation Controls MDA-MB-231 Breast Cancer Cell Invasion through the Modulation of Endoplasmic Reticulum Stress

“…Finally, we demonstrated that the overall survival rate was severely reduced in breast cancer patients in whom the expression levels of ATAT1 and the five aforementioned genes were negatively correlated. Therefore, analysis of the expression levels of these genes will be useful for the diagnosis of triple-negative malignant breast tumors in future, and inhibition of microtubule acetylation might be a useful strategy for triple-negative breast cancer treatment [ 50 ].…”

A phospho-regulated signal motif determines subcellular localization of α-TAT1 for dynamic microtubule acetylation

“…While there are pharmacological agents that promote increased MT acetylation through inhibition of deacetylases, currently there are no available pharmacological inhibitors of α -TAT1 itself, although there appears to be a considerable interest in the development of such inhibitors 74 . Identifying a small chemical targeted to the C-terminus signal motif to alter the subcellular localization, instead of the catalytic activity, may open up a novel approach for inhibiting MT acetylation.…”