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Anti-tumour activity of phosphoinositide-3-kinase antagonist AEZS 126 in models of triple-negative breast cancer

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Abstract

Purpose

Of more than one million global cases of breast cancer diagnosed each year, a high percentage are characterized as triple-negative, lacking the oestrogen, progesterone and Her2/neu receptors. The incidence exceeds the incidence of malignancies like CML by far. Lack of effective therapies, younger age at onset and early metastatic spread have contributed to the poor prognosis and outcomes associated with these malignancies.

Methods

Here, we investigate the ability of the PI3K/AKT inhibitor AEZS 126 to selectively target the triple-negative breast cancer (TNBC) cell proliferation and survival in vitro by MTT-assays and FACS-based analysis. Furthermore, the mechanism of cytotoxicity is analysed by FACS-based assays and Western blots.

Results

AEZS 126 showed good anti-tumour activity in in vitro models of TNBC as well as in MCF-7 cells. Main mechanism of cytotoxicity seems to be programmed cell death after an incubation time of 72 h, which could be abrogated by co-incubation with z-VAD-fmk in MCF-7 and MDA-MB468 cells. In HCC1806 cells, addition of necrostatin-1 has only slightly protective effects, but in HCC1937 cells, the addition of necrostatin-1 has the same protective effect as co-incubation with z-VAD-fmk, and this observation argues for cell death caused by apoptosis and necroptosis in this cell line.

Conclusion

We demonstrated the highly efficient anti-tumour activity of AEZS 126 in in vitro models of TNBC. Due to the good anti-tumour activity and the expected favourable toxicity profile, AEZS 126 in combination with chemotherapy seems to be a promising candidate for clinical testing in TNBC especially in the basal-like subgroup of TNBC.

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Acknowledgments

We appreciate the permission to use the INTAS ChemoStar Imager (Department of Microbiology, University of Würzburg). Therefore, we thank especially Prof. Rudel and Dr. Bergmann. This work was supported by a grant from IZKF (Interdiziplinäres Zentrum für Klinische Forschung; University of Würzburg).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Gynecology, Medical University of Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany

    Jens C. Hahne, Heike Schmidt, Susanne R. Meyer, Johannes Dietl & Arnd Honig

  2. Department of Gynecology, University of Regensburg, Landshuter Str. 65, 93055, Regensburg, Germany

    Jörg B. Engel

Authors
  1. Jens C. Hahne
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  2. Heike Schmidt
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  3. Susanne R. Meyer
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  4. Jörg B. Engel
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  5. Johannes Dietl
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  6. Arnd Honig
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Correspondence to Arnd Honig.

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Hahne, J.C., Schmidt, H., Meyer, S.R. et al. Anti-tumour activity of phosphoinositide-3-kinase antagonist AEZS 126 in models of triple-negative breast cancer. J Cancer Res Clin Oncol 139, 905–914 (2013). https://doi.org/10.1007/s00432-013-1399-z

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