The effects of PKI-402 on breast tumor models’ radiosensitivity via dual inhibition of PI3K/mTOR

Abstract

Purpose

PI3K/Akt/mTOR pathway activation causes relapse and resistance after radiotherapy in breast cancer (BC). We aimed to radiosensitize BC cell lines to irradiation (IR) by PKI-402, a dual PI3K/mTOR inhibitor.

Methods

We performed cytotoxicity, clonogenicity, hanging drop, apoptosis and double-strand break detection, and phosphorylation of 16 essential proteins involved in the PI3K/mTOR pathway.

Results

Our findings showed that PKI-402 has cytotoxic efficiency in all cell lines. Clonogenic assay results showed that PKI-402 plus IR inhibited the colony formation ability of MCF-7 and breast cancer stem cell lines. Results showed that PKI-402 plus IR causes more apoptotic cell death than IR alone in the MCF-7 cells but did not cause significant changes in the MDA-MB-231. γ-H2AX levels were increased in MDA-MB-231 in PKI-402 plus IR groups, whereas we did not observe any apoptotic and γ-H2AX induction in BCSCs and MCF-10A cells in all treatment groups. Some pivotal phosphorylated proteins of the PI3K/AKT pathway decreased, several proteins increased and others did not change.

Conclusion

In conclusion, if the combined use of PKI-402 with radiation is supported by in vivo studies, it can contribute to the treatment options and the course of the disease.

Keywords:

• Breast cancer
• radiosensitivity
• PI3K/mTOR pathway
• PKI-402

Acknowledgments

This study was performed thanks to the Ege University Scientific Research Projects (BAP) Department’s financial support. We are also thankful to Ege University Pharmaceutical Sciences Research Center (FABAL) and Ege University Faculty of Medicine Radiation Oncology Department for supplying Odyssey Imaging Systems and 6 MV linac-linear accelerator Precise Treatment System™ – TrueBeam, respectively.

Disclosure statement

The authors have no conflicts of interest to declare.

Additional information

Funding

This study was supported by Ege University Scientific Research Projects (BAP) Department (Grant No. 2017-TIP-022, 18-KSUAM-001).

Notes on contributors

Roya Gasimli

Roya Gasimli is a PhD candidate, Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey.

Cagla Kayabasi

Cagla Kayabasi is a postdoctoral researcher, Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey.

Besra Ozmen Yelken

Besra Ozmen Yelken is an assistant professor, Department of Medical Biology, Faculty of Medicine, Bakircay University, Izmir, Turkey

Aycan Asik

Aycan Asik is a research assistant, Department of Medical Biology, Faculty of Medicine, Muğla Sıtkı Koçman University, Mugla, Turkey.

Fatma Sogutlu

Fatma Sogutlu is a PhD candidate, Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey.

Caglar Celebi

Caglar Celebi is a PhD candidate, Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey.

Sunde Yilmaz Susluer

Sunde Yilmaz Susluer is an associate professor, Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey.

Serra Kamer

Serra Kamer is a professor, Department of Radiation Oncology, Faculty of Medicine, Ege University, Izmir, Turkey.

Cigir Biray Avci

Cigir Biray Avci is an associate professor, Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey

Ayfer Haydaroglu

Ayfer Haydaroglu is a professor, Department of Radiation Oncology, Faculty of Medicine, Ege University, Izmir, Turkey

Cumhur Gunduz

Cumhur Gunduz is a professor, Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey