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.

• Authors: Roya Gasimli, Cagla Kayabasi, Besra Ozmen Yelken, Aycan Asik, Fatma Sogutlu, Caglar Celebi, Sunde Yilmaz Susluer, Serra Kamer, Cigir Biray Avci, Ayfer Haydaroglu, Cumhur Gunduz
• Journal: International journal of radiation biology (Int J Radiat Biol) Vol. 99 Issue 12 Pg. 1961-1970 ( 2023) ISSN: 1362-3095 [Electronic] England
• PMID: 37389464 (Publication Type: Journal Article)

Chemical References

• Phosphatidylinositol 3-Kinases
• PKI 402
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Phosphoinositide-3 Kinase Inhibitors

Topics

• Humans
• Female
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Cell Proliferation (radiation effects)
• Neoplasm Recurrence, Local
• TOR Serine-Threonine Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors (pharmacology)
• Breast Neoplasms (radiotherapy, pathology)
• Radiation Tolerance
• Apoptosis
• Cell Line, Tumor