Docetaxel-induced polyploidization may underlie chemoresistance and disease relapse

• Type of Material: Article
• Authors: Angela Ogden, Georgia State University; Padmashree C.G. Rida, Georgia State University; Beatrice Knudsen, Cedars Sinai Medical Center; Omer Kucuk, Emory University; Ritu Aneja, Georgia State University
• Language: English
• Date: 2015-10-28
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Ireland Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.canlet.2015.06.025
• Title of Journal or Parent Work: Cancer Letters
• ISSN: 0304-3835
• Volume: 367
• Issue: 2
• Start Page: 89
• End Page: 92
• Grant/Funding Information: This work was supported, in whole or in part, by the National Cancer Institute grant 3R01CA169127-03S1 (RA) and the Georgia State University Molecular Basis of Disease Area of Focus graduate fellowship (AO).
• Keywords: Science & Technology; Life Sciences & Biomedicine; INDUCTION; Chemoresistance; Centrosome declustering; THERAPY; NEOSIS; GROWTH; CANCER-CELLS; INDUCED SENESCENCE; Polyploidy; Oncology; Recurrence; Docetaxel
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

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.