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Open Access Highly Accessed Research article

Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells

Eduardo C Filippi-Chiela1, Marcos Paulo Thomé1, Mardja Manssur Bueno e Silva1, Alessandra Luíza Pelegrini1, Pitia Flores Ledur1, Bernardo Garicochea45, Lauren L Zamin3 and Guido Lenz12*

Author Affiliations

1 Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Bento Gonçalves, 9500, Prédio 43431 – Lab. 107, Porto Alegre, RS CEP 91501-970, Brazil

2 Center of Biotechnology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

3 Universidade Federal da Fronteira Sul (UFFS), Cerro Largo, RS, Brazil

4 Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil

5 Oncology Center - Hospital Sirio Libanes, Sao Paulo, SP, Brazil

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BMC Cancer 2013, 13:147  doi:10.1186/1471-2407-13-147

Published: 22 March 2013

Abstract

Background

Temozolomide (TMZ) is the most widely used drug to treat glioblastoma (GBM), which is the most common and aggressive primary tumor of the Central Nervous System and one of the hardest challenges in oncotherapy. TMZ is an alkylating agent that induces autophagy, apoptosis and senescence in GBM cells. However, therapy with TMZ increases survival after diagnosis only from 12 to 14.4 months, making the development of combined therapies to treat GBM fundamental. One candidate for GBM therapy is Resveratrol (Rsv), which has additive toxicity with TMZ in several glioma cells in vitro and in vivo. However, the mechanism of Rsv and TMZ additive toxicity, which is the aim of the present work, is not clear, especially concerning cell cycle dynamics and long term effects.

Methods

Glioma cell lines were treated with Rsv and TMZ, alone or in combinations, and the induction and the role of autophagy, apoptosis, cell cycle dynamics, protein expression and phosphorylation status were measured. We further evaluated the long term senescence induction and clonogenic capacity.

Results

As expected, temozolomide caused a G2 cell cycle arrest and extensive DNA damage response. Rsv did not reduced this response, even increasing pATM, pChk2 and gammaH2Ax levels, but abrogated the temozolomide-induced G2 arrest, increasing levels of cyclin B and pRb(S807/811) and reducing levels of pWee1(S642) and pCdk1(Y15). This suggests a cellular state of forced passage through G2 checkpoint despite large DNA damage, a scenario that may produce mitotic catastrophe. Indeed, the proportion of cells with high nuclear irregularity increased from 6 to 26% in 48 h after cotreatment. At a long term, a reduction in clonogenic capacity was observed, accompanied by a large induction of senescence.

Conclusion

The presence of Rsv forces cells treated with TMZ through mitosis leading to mitotic catastrophe and senescence, reducing the clonogenic capacity of glioma cells and increasing the chronic effects of temozolomide.

Keywords:
Glioblastoma; Resveratrol; Temozolomide; Autophagy; Mitotic Catastrophe; Senescence