Oncotarget

Research Papers:

MEK-inhibitor PD184352 enhances the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922: the role of cell type and drug-irradiation schedule

Felix Grabenbauer, Astrid Katzer, Dmitri Sisario, Simon Memmel, Michael Flentje, Vladimir L. Sukhoruko and Cholpon S. Djuzenova _

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Oncotarget. 2018; 9:37379-37392. https://doi.org/10.18632/oncotarget.26436

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Abstract

Felix Grabenbauer1, Astrid Katzer1, Dmitri Sisario2, Simon Memmel1, Michael Flentje1,*, Vladimir L. Sukhorukov2,* and Cholpon S. Djuzenova1,*

1Department of Radiation Oncology, University Hospital of Würzburg, Würzburg, Germany

2Department of Biotechnology and Biophysics, University of Würzburg, Würzburg, Germany

*These (senior) authors contributed equally to this work

Correspondence to:

Cholpon S. Djuzenova, email: djuzenova_t@ukw.de

Keywords: cell cycle arrest; colony survival; DNA damage; histone γH2AX; radiation sensitivity

Received: August 09, 2018    Accepted: November 26, 2018    Published: December 21, 2018

ABSTRACT

Targeting MEK protein in cancer cells usually leads to acquired resistance to MEK inhibitors and activation of the prosurvival protein Akt. Since both MEK and Akt are clients of the Hsp90 chaperone system, the present study explores the responses of irradiated lung carcinoma A549 and glioblastoma SNB19 cell lines to combined MEK and Hsp90 inhibition. Unexpectedly, the MEK inhibitor PD184352 administered 24 h prior to irradiation, enhanced cell survival through upregulation of not only MEK and Erk1/2 but also of Akt. In contrast, PD184352 added 1 h before irradiation strongly reduced the expression of Erk and did not upregulate Akt in both cell lines. As a result, the MEK inhibitor increased the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in glioblastoma SNB19 cells. Possible reasons for the enhanced cell killing under this short-term pretreatment schedule may be a down-regulation of Erk during or directly after irradiation, increased DNA damage and/or a strong G2/M arrest 24 h after irradiation. In addition, an 1-h pretreatment with PD184352 and/or NVP-AUY922 under schedule II induced neither G1 arrest nor up-regulation of p-Akt in both cell lines as it did under schedule I. Yet, a long-term treatment with the MEK inhibitor alone caused a strong cytostatical effect. We conclude that the duration of drug pretreatment before irradiation plays a key role in the targeting of MEK in tumor cells. However, due to an aberrant activation of prosurvival proteins, the therapeutic window needs to be carefully defined, or a combination of inhibitors should be considered.


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