title: Docetaxel-induced polyploidization may underlie chemoresistance and disease relapse.
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 combatted 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.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Ogden
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Padmashree C G
authors.initials: PC
authors.lastname: Rida
authors.affiliation: Translational Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Beatrice S
authors.initials: BS
authors.lastname: Knudsen
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Omer
authors.initials: O
authors.lastname: Kucuk
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA; Institute of Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA. Electronic address: raneja@gsu.edu.
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016922:Cellular Senescence / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015726:Giant Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011123:Polyploidy; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000009:adverse effects*; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel
keywords: Centrosome declustering; Chemoresistance; Docetaxel; Polyploidy; Recurrence