2-methoxyestradiol sensitizes breast cancer cells to taxanes by targeting centrosomes
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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
Keywords: breast cancer; 2-methoxyestradiol (2-ME); centrosome amplification; centrosome declustering
Received: July 22, 2020 Accepted: October 27, 2020 Published: December 01, 2020
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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