9-bromonoscapine-induced mitotic arrest of cigarette smoke condensate-transformed breast epithelial cells.
In the present investigation, we determined the chemotherapeutic efficacy of 9-bromonoscapine (Br-Nos), a more potent noscapine analog, on MCF10A, spontaneously immortalized human normal breast epithelial cells and MCF10A-CSC3, cigarette smoke condensate (CSC)-transformed cells. The results from cytogenetic analysis showed that Br-Nos induced polyploidy and telomeric association in MCF10A-CSC3 cells, while MCF10A cells remained unaffected. Our immunofluorescence data further demonstrated that MCF10A-CSC3 cells were susceptible to mitotic catastrophe on exposure to Br-Nos and failed to recover after drug withdrawal. MCF10A-CSC3 cells exhibited Br-Nos-induced aberrant multipolar spindle formation, which irreversibly impaired the alignment of replicated chromosome to the equatorial plane and finally culminated in cell death. Although MCF10A cells upon Br-Nos treatment showed bipolar spindles with some uncongressed chromosomes, these cells recovered fairly well after drug withdrawal. Our flow-cytometry analysis data reconfirmed that MCF10A-CSC3 cells were more susceptible to cell death compared to MCF10A cells. Furthermore, our results suggest that decreased levels of cdc2/cyclin B1 and cdc2 kinase activity are responsible for Br-Nos-induced mitotic cell arrest leading to cell death in MCF10A-CSC3 cells. This study thus explores the underlying mechanism of Br-Nos-induced mitotic catastrophe in CSC-transformed MCF10A-CSC3 cells and its potential usefulness as a chemotherapeutic agent for prevention of cigarette smoke-induced breast cancer growth.
Jaiswal
Aruna S
AS
Department of Anatomy and Cell Biology and UF Shands Cancer Center, University of Florida, Gainesville, Florida 32610, USA.
Aneja
Ritu
R
Connors
Shahnjayla K
SK
Joshi
Harish C
HC
Multani
Asha S
AS
Pathak
Sen
S
Narayan
Satya
S
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D019926:Cyclin B; D056744:Cyclin B1; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D009665:Noscapine / Q000031:analogs & derivatives / Q000494:pharmacology; D012906:Smoke; D008941:Spindle Apparatus / Q000187:drug effects; D014026:Nicotiana / Q000737:chemistry*
D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D012906:Smoke; D009665:Noscapine; D016203:CDC2 Protein Kinase