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Potent Small-Molecule Inhibitors Targeting Acetylated Microtubules as Anticancer Agents Against Triple-Negative
Ahreum Kwon1, Gwi Bin Lee2, Taein Park2
1Cell Logistics and Silver Health Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea.
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.
Insights
Researchers discovered new chemicals that specifically target acetylated microtubules, a hallmark of triple-negative breast cancer (TNBC). These compounds selectively kill cancer cells, offering a promising new therapeutic strategy for TNBC treatment.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Microtubules are crucial for cell proliferation and migration, making them a key target for anticancer drugs.
- Current microtubule-targeting drugs cause side effects due to toxicity to normal cells.
- Developing cancer-specific microtubule agents is essential for improved therapeutic outcomes.
Purpose of the Study:
- To identify novel chemical compounds that selectively target acetylated microtubules.
- To investigate the potential of these compounds as therapeutic agents for triple-negative breast cancer (TNBC).
Main Methods:
- Chemical screening for compounds binding to acetylated microtubules.
- Assessing the effect of compounds on microtubule acetylation and cell apoptosis in TNBC and non-TNBC cell lines.
- Evaluating tumor growth inhibition in mouse xenograft models.
Main Results:
- Identified chemical compounds that specifically bind to acetylated microtubules.
- Compounds interfered with alpha-tubulin acetyltransferase 1 (αTAT1) access, disrupting acetylated microtubule lattices.
- Demonstrated increased apoptotic cell death in TNBC cells (MDA-MB-231) compared to non-TNBC cells (MCF-10A, MCF-7).
- Significant reduction in tumor growth observed in mouse xenograft models.
Conclusions:
- The identified chemical compounds exhibit selectivity for acetylated microtubules.
- These compounds represent potential therapeutic agents for treating TNBC by targeting microtubule acetylation.
- This approach offers a strategy for developing cancer-specific microtubule-targeting therapies.
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