Oncotarget

Research Papers:

2-methoxyestradiol sensitizes breast cancer cells to taxanes by targeting centrosomes

Randa El-Zein _, Jose Thaiparambil and Sherif Z. Abdel-Rahman

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Oncotarget. 2020; 11:4479-4489. https://doi.org/10.18632/oncotarget.27810

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Abstract

Randa El-Zein1,2, Jose Thaiparambil1 and Sherif Z. Abdel-Rahman3

1 Houston Methodist Cancer Center, Houston, TX 77030, USA

2 Department of Radiology, Houston Methodist Research Institute, Houston, TX 77555, USA

3 Department of Obstetrics and Gynecology, Maternal-Fetal Pharmacology and Biodevelopment Laboratories, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA

Correspondence to:

Randa El-Zein,email: rel-zein2@methodistmethodist.org

Keywords: breast cancer; 2-methoxyestradiol (2-ME); centrosome amplification; centrosome declustering

Received: July 22, 2020     Accepted: October 27, 2020     Published: December 01, 2020

Copyright: © 2020 El-Zein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Centrosomes amplification is a hallmark of cancer. We hypothesize that 2-methoxyestradiol (2-ME) sensitizes breast cancer (BC) cells to taxanes by targeting amplified centrosomes. We assessed the extent by which 2-ME together with paclitaxel (PTX) induces centrosome alterations with subsequent mitotic catastrophe in different BC subtypes. 2-ME induced a significant reduction in PTX IC50 values in all cells tested ranging from 28–44% (P < 0.05). Treatment with both PTX and 2-ME significantly increased the number of misaligned metaphases compared to PTX alone (34%, 100% and 52% for MCF7, MDA-MB231 and SUM149, respectively; P < 0.05). The number of cells with multipolar spindle formation was significantly increased (81%, 220% and 285% for MCF7, MDA-MB231 and SUM 149, respectively; P < 0.05). PTX and 2-ME treatment significantly increased interphase declustering in cancer cells (56% for MCF7, 208% for MDA-MB231 and 218% for SUM149, respectively; P < 0.05) and metaphase declustering (1.4-fold, 1.56-fold and 2.48-fold increase for MCF7, MDA-MB231 and SUM149, respectively; P < 0.05). This report is the first to document centrosome declustering as a mechanism of action of 2-ME and provides a potential approach for reducing taxane toxicity in cancer treated patients.


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