Biochemical effects of combined action of ?-irradiation and paclitaxel on anaplastic thyroid cancer cells

V M Pushkarev,M D Tronko,V V Pushkarev,O I Kovzun

doi:10.15407/ubj85.01.051

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.

Highlights

In anaplastic thyroid cancer (ATC) cells the ionizing radiation and Ptx exhibited competitive effects upon phosphorylation of cell cycle controllers: p53, pRb, CHK2, cAbl and expression of Вах
It was shown that Ptx activated caspase-9 in ATC cells [7, 17], indicating the induction of mitochondrial pathway of apoptosis
It is believed that this is the main mechanism of apoptosis induction, more important than the pathway through death receptors and caspase-8 activation, the latter beingrealized only in some ATC cell lines [7]

Summary

Introduction

In ATC cells the ionizing radiation and Ptx exhibited competitive effects upon phosphorylation of cell cycle controllers: p53, pRb, CHK2, cAbl and expression of Вах. The combined effect of radiation and Ptx enhanced antiapoptotic Bcl-2 phosphorylation, caspases activation and survivin expression. We have shown the combined effect of Ptx and ionizing radiation (IR) in vivo in one of the most aggressive human tumors, anaplastic thyroid cancer (ATC) [3]. IR enhanced the effect of Ptx, and after 20 days of treatment tumors in mice disappeared. It seems that a combination of chemotherapy and DNA-damaging agents may be effective for ATC treatment. We attempted to elucidate the biochemical mechanisms of combined action of Ptx and IR in ATC cells in vitro

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Conclusion