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Submitted on February 2, 2004
Accepted on March 19, 2004
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan (V.M.P, D.V.S, V.A.S, H.N., S.Y.); Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kiev, Ukraine (V.M.P., M.D.T.), Kawasaki Medical School, Kawasaki, Japan (J.K.)
* To whom correspondence should be addressed. E-mail: shun{at}net.nagasaki-u.ac.jp.
Understanding the detailed mechanisms of a chemotherapeutic agent action on cancer cells is essential for planning the clinical applications since drug effects are often tissue- and cell-type specific. This study was set out to elucidate the molecular pathways of Taxol effects in human anaplastic thyroid cancer (ATC) cells using as an experimental model four cell lines, ARO, KTC-2, KTC-3 (anaplastic thyroid cancer), FRO (undifferentiated follicular cancer) and primary thyrocytes.
All cell lines were sensitive to Taxol although to different extent. In primary thyrocytes the drug displayed substantially lower cytotoxicity. In thyroid cancer cells Taxol induced changes characteristic to apoptosis such as PARP and procaspase cleavage and alteration of membrane asymmetry only within a narrow concentration range, from 6 to 50 nM. At higher concentration, other form(s) of cell death perhaps associated with mitochondrial collapse was observed. Low doses of Taxol enhanced Bcl2 phosphorylation and led to its degradation observed on the background of a sustained or increasing Bax level and accumulation of survivin and XIAP. JNK activation was essential for the apoptosis in ATC cells whereas Raf/MEK/ERK and PI3K/Akt were likely to comprise main survival mechanisms.
Our results suggest an importance of cautious interpreting of biological effects of Taxol in laboratory studies and for determining optimal doses of Taxol to achieve the desired therapeutic effect in anaplastic thyroid cancers.
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