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Analysis of Cell-Cycle Checkpoint Pathways in Head and Neck Cancer Cell Lines
Implications for Therapeutic Strategies
Sean C. Coleman, MD;
Zoe A. Stewart, PhD;
Terry A. Day, MD;
James L. Netterville, MD;
Brian B. Burkey, MD;
Jennifer A. Pietenpol, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:167-176.
Objective To determine the mechanism of action of paclitaxel (Taxol) and carboplatin
in cell lines of head and neck squamous cell carcinoma (HNSCC).
Design Four HNSCC cell lines were treated with paclitaxel and carboplatin,
alone or in combination, and evaluated for cell-cycle position by means of
flow cytometry, for molecular determinants of cell cycle by means of Western
blotting and kinase analysis, and for anchorage-independent growth by means
of soft-agar assays.
Results Paclitaxel was more effective at inducing apoptosis and inhibiting anchorage-independent
cell growth, compared with carboplatin. The activity of paclitaxel was correlated
with an elevation of cyclin B1/CDC2 activity, prolonged mitotic arrest, and
Bcl-2 phosphorylation. In contrast, carboplatin arrested cells before mitosis.
Combination treatment with both agents, simultaneously or sequentially, was
more effective at inhibiting cell growth than either single agent. Cellular
outcome was the same regardless of which drug was used first. The order of
addition of these 2 drugs differentially affected cell-cycle position. Paclitaxel
pretreatment arrested cells in mitosis, whereas carboplatin pretreatment or
cotreatment resulted in premitotic arrest.
Conclusions To our knowledge, this study is the first to explore how paclitaxel
and carboplatin, alone or in combination, differentially affect cell-cycle
checkpoint response and HNSCC cell growth. These results provide molecular
validation for the current clinical use of both drugs in combination and set
the stage for analyses of patient tumor specimens.
From the Vanderbilt Bill Wilkerson Center for Otolaryngology and Communication
Sciences, Department of Otolaryngology (Drs Coleman, Day, Netterville, and
Burkey), the Department of Biochemistry (Drs Stewart and Pietenpol), the Center
in Molecular Toxicology (Dr Pietenpol), and the Vanderbilt-Ingram Cancer Center
(Dr Pietenpol), Vanderbilt University School of Medicine, Nashville, Tenn.
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Archives of Otolaryngology–Head & Neck Surgery Reader's Choice: Continuing Medical Education
Arch Otolaryngol Head Neck Surg. 2002;128(2):202-203.
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