Abstract
The aim of the paper was to describe the biochemical effects of Paclitaxel (Ptx), gamma-irradiation (IR) and their combination in undifferentiated thyroid cancer cells (ATC). IR activated common DNA damage-induced signaling and manifested certain mitogenic effect by inactivation of retinoblastoma protein (pRb). There was clear antagonism between Ptx and IR relative to cell cycle regulators--tumor suppressor p53, pRb, CHK2 and c-Abl as well as proapoptotic Bax expression, but combined action of both agents enhanced caspase-3 and, especially, caspase-8 activation. The Ptx at low (1-25 nM) concentrations caused noticeable radioprotective effect. Thus, in ATC cells the ionizing radiation and Ptx exhibited competitive effects upon phosphorylation of cell cycle controllers: p53, pRb, CHK2, cAbl and expression of Bax. At the same time, the combined effect of radiation and Ptx enhanced antiapoptotic Bcl-2 phosphorylation, caspases activation and survivin expression. The net effect of these events during the first 48-72 h of cells incubation can be considered as antiapoptotic--Ptx attenuated cytotoxic effect of IR.
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Caspase 8 / genetics
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Caspase 8 / metabolism
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Cell Line, Tumor
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Checkpoint Kinase 2
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Combined Modality Therapy / adverse effects
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Dose-Response Relationship, Drug
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Gamma Rays*
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Expression Regulation, Neoplastic / radiation effects*
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Humans
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Paclitaxel / pharmacology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism
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Signal Transduction / drug effects
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Signal Transduction / radiation effects
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Survivin
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Thyroid Carcinoma, Anaplastic
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Thyroid Neoplasms / drug therapy
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Thyroid Neoplasms / genetics*
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Thyroid Neoplasms / pathology
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Thyroid Neoplasms / radiotherapy
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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BIRC5 protein, human
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Inhibitor of Apoptosis Proteins
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Proto-Oncogene Proteins c-bcl-2
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Retinoblastoma Protein
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Survivin
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Tumor Suppressor Protein p53
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Checkpoint Kinase 2
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Proto-Oncogene Proteins c-abl
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CHEK2 protein, human
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Protein Serine-Threonine Kinases
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Caspase 3
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Caspase 8
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Paclitaxel