Docetaxel-induced polyploidization may underlie chemoresistance and disease relapse

作者：Ogden Angela; Rida Padmashree C G; Knudsen Beatrice S; Kucuk Omer; Aneja Ritu^*

来源：Cancer Letters, 2015, 367(2): 89-92.

DOI：10.1016/j.canlet.2015.06.025

• Docetaxel
• Polyploidy
• Recurrence
• Chemoresistance
• Centrosome declustering

Although docetaxel significantly improves survival in a variety of malignancies, its clinical utility is severely restricted by acquired chemoresistance and disease relapse. To uncover the mechanisms underlying these all too common occurrences, an abundance of research has focused on mutations and gene expression patterns; however, these findings are yet to translate into improved outcomes for patients being administered this drug. These analyses have overlooked a promising lead in the quest to discern key mediators of resistance and relapse following docetaxel therapy: polyploidization. This process is manifested following docetaxel-mediated mitotic arrest by the appearance of giant, multinucleated cells, which slipped from mitosis without undergoing cytokinesis. Polyploid cells generally possess supernumerary centrosomes, are chromosomally instable, and resist chemotherapy. We thus suspect that chemoresistance and relapse following treatment with docetaxel might be combated by co-administration of centrosome declustering drugs, which could selectively destroy polyploid cells given that normal cells do not possess amplified centrosomes, an intriguing paradigm that warrants further investigation.

• 出版日期2015-10-28