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.
Highlights
Despite recent advances in early detection and treatment, breast cancer (BC) remains a major public health problem worldwide
The Basal type is not repsonsive to hormone therapy but is often responsive to chemotherapy, while the human epidermal growth factor receptor 2 (HER2) amplified is often reponsive to HER2 antibody and chemotherapy [3]
It is reported that taxanes act mainly through: a) interference with microtubule polymerization, leading to cell cycle arrest at mitosis [7]; b) phosphorylation and inactivation of the anti-apoptotic Bcl-2 protein, leading to the induction of caspase-dependent apoptosis [8]
Summary
Despite recent advances in early detection and treatment, breast cancer (BC) remains a major public health problem worldwide. In the US, BC is the most common cancer among women, accounting for 30% of newly diagnosed cancers. Luminal A subtype is responsive to hormone therapy and often to chemotherapy. Luminal B is usualy responsive to hormone and chemotherapy with variable response to HER2 antibody therapies. The Basal type is not repsonsive to hormone therapy but is often responsive to chemotherapy, while the HER2 amplified is often reponsive to HER2 antibody and chemotherapy [3]. Since taxane usefulness is limited due to their toxic side effects and de-novo refractoriness (acquired tumor resistance), it is imperative to develop better treatment strategies to improve patients response and prognosis to these therapeutics
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