Background
Heat shock protein 90 (HSP90) is a chaperone protein regulating several client proteins
involved in thyroid cancer development. The purpose of this study was to mechanistically
evaluate a novel, natural product drug with anticancer activity in thyroid cancer
cell lines in vitro for future translational applications.
Methods
A total of 285 natural plant extracts and compounds were evaluated for anticancer
activity by MTS assay. Apoptosis and cell cycle arrest were characterized by annexin
V-propidium iodide (PI) flow cytometry. HSP90 and client protein modulation, as well
as apoptosis confirmation, as demonstrated by Western blot analysis.
Results
Of the 285 compounds and products tested, 45 demonstrated antiproliferative activity
in thyroid cancers by MTS assay. BTIMNP_D004 demonstrated the greatest inhibition
(IC50 = 155–2,890 nM in thyroid cancers). Activity was cancer-cell selective compared to
fibroblasts, with increased potency over 17-AAG in BCPAP, FTC133, and DRO81-1 cells.
D004 modulated cell cycle arrest after 18 hours (G1/G0 → S and G2/M) with 30% FTC133 cells shifted, 22% BCPAP cells shifted, and 15% SW1736 cells shifted
versus controls (P < .01, P < .01, and P < .05, respectively). A total of 1 μM D004 induced significant apoptosis, with 76%
BCPAP cells gated after 18 hours (annexin V-PI staining vs <3% in controls, P < .01; and 80% FTC133 cells vs 4% controls; P < .01). Western blot analysis demonstrated modulation of HSP90 expression levels,
with inhibition of HSF-1, AKT, and caspase-3 expression, and cleavage of PARP in both
BCPAP and FTC133 cells.
Conclusion
BTIMNP_D004 is a novel natural product drug with anticancer activity against thyroid
cancers in vitro, and may act through induction of apoptosis, modulation of cell cycle
arrest, and modulation of heat shock chaperone proteins including HSP90. These preliminary
in vitro data support future preclinical studies for translational applications.
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Article info
Footnotes
Presented at the 30th Annual Meeting of the American Association of Endocrine Surgeons, Madison, Wisconsin, May 2–5, 2009.
Supported in part by research grants from the National Institutes of Health (P20 RR016443 to B.N.T. and M.S.C.) through the University of Kansas Center for Cancer Experimental Therapeutics (CCET) National Institutes of Health Center of Biomedical Research Excellence (COBRE) Program.
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Copyright
© 2009 Published by Elsevier Inc.
