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Targeting the phosphoinositide 3-kinase/AKT pathways by small molecules and natural compounds as a therapeutic approach for breast cancer cells

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Abstract

The phosphoinositide 3-kinase/AKT/mTOR (PI3K/AkT/mTOR) pathway plays a pivotal role in the uncontrolled growth, migration and development of human breast cancer. The elevated expression of TGF-β1 increases the PI3K/AkT/mTOR activity in human breast cancer tissue and potentially motivates tumor metastasis and resistance to chemotherapy. Here, we investigated whether treatment with PI3K/AkT/mTOR dual inhibitor NVP-BEZ235 alone or in combination with caffeic acid phenyl ester (CAPE) could prevent TGF-β1 effects on breast cancer cells. MCF-7 human breast cancer cells were exposed to TGF-β1 for 14 days and then were treated with/without NVP-BEZ235 and/or CAPE. Cell viability, apoptosis, CXCR4 surface expression and mRNA levels of CXCR4 and TWIST-1 were analyzed in all treated groups. We found that treatment of human breast cancer cells with a combination of NVP-BEZ235 and CAPE increased induction of cellular death. Although flow cytometry analysis demonstrated that NVP-BEZ235 alone treatment reduced CXCR4 expression while increasing CXCR4 mRNA level; when NVP-BEZ235 was combined with CAPE, inhibition of CXCR4 surface expression and enhancement of CXCR4 mRNA expression was diminished. In addition, TWIST-1 mRNA expression was down regulated in samples treated with both NVP-BEZ235 and CAPE. These altogether signified that NVP-BEZ235 in combination with CAPE showed improved therapeutic efficacy in breast cancer cells by decreasing apoptotic resistance and reduction of CXCR4 and TWIST-1 expression at mRNA level could be one of mechanism of action.

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Acknowledgements

The authors wish to express their deep appreciation to Cellular and Molecular Research Center staff of Shahrekord University of Medical Science.

Funding

This study was funded by Shahrekord University of Medical Sciences (Grant Number 2176).

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Authors and Affiliations

  1. Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Amin Soltani

  2. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, PO Box 88155-571, Shahrekord, Iran

    Samira Torki & Mahdi Ghatrehsamani

  3. Department of Microbiology and Immunology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Milad Sabzevary Ghahfarokhi

  4. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA

    Mohammad Saied Jami

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  1. Amin Soltani
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  2. Samira Torki
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  3. Milad Sabzevary Ghahfarokhi
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  4. Mohammad Saied Jami
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  5. Mahdi Ghatrehsamani
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Correspondence to Mahdi Ghatrehsamani.

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Soltani, A., Torki, S., Ghahfarokhi, M.S. et al. Targeting the phosphoinositide 3-kinase/AKT pathways by small molecules and natural compounds as a therapeutic approach for breast cancer cells. Mol Biol Rep 46, 4809–4816 (2019). https://doi.org/10.1007/s11033-019-04929-x

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  • DOI: https://doi.org/10.1007/s11033-019-04929-x

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