9-bromonoscapine-induced mitotic arrest of cigarette smoke condensate-transformed breast epithelial cells

J Cell Biochem. 2009 Apr 15;106(6):1146-56. doi: 10.1002/jcb.22099.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / chemically induced*
  • Cyclin B
  • Cyclin B1
  • Epithelial Cells* / cytology
  • Epithelial Cells* / drug effects
  • Epithelial Cells* / physiology
  • Female
  • Humans
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / drug effects
  • Mammary Glands, Human / metabolism
  • Mitosis / drug effects*
  • Noscapine* / analogs & derivatives
  • Noscapine* / pharmacology
  • Smoke*
  • Spindle Apparatus / drug effects
  • Tobacco / chemistry*

Substances

  • Antineoplastic Agents
  • CCNB1 protein, human
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclin B1
  • Smoke
  • Noscapine
  • CDC2 Protein Kinase