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Dual PI3K/mTOR inhibitor, XL765 (SAR245409), shows superior effects to sole PI3K [XL147 (SAR245408)] or mTOR [rapamycin] inhibition in prostate cancer cell models

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Tumor Biology

Abstract

Deregulation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway contributes to prostate cancer development and progression. Here, we compared the in vitro effects of the dual PI3K/mTOR inhibitor (XL765) with those observed with the sole PI3K (XL147) or mTOR (rapamycin) inhibition in 2 non-tumor prostate epithelial cell lines, 8 prostate cancer cell lines, and 11 prostate cancer cell derivatives. We demonstrated that the XL765 treatment showed superior and proliferative effects of XL147 or rapamycin. The XL765 effects were associated to increasing the chromosome region maintenance 1 (CRM1)-mediated nuclear localization of glycogen synthase kinase 3 beta (GSK3β) and Foxo-1a with higher induction of apoptosis when compared to those observed in XL147 and rapamycin treatments. IC50 values were calculated in phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-positive and PTEN-negative cell lines as well as after PTEN transfection or PTEN downmodulation by siRNA strategy revealing that the presence of this protein was associated with reduced sensitivity to PI3K and mTOR inhibitors. The comparison of IC50 values was also calculated for androgen-dependent and -independent cell lines as well as after androgen receptor (AR) transfection or the AR downmodulation by siRNA strategy revealing that androgen independence was associated with enhanced responsiveness. Our results provide a rationale to use the dual PI3K/Akt/mTOR inhibitors in hormone-insensitive prostate cancer models due to the overactivity of PI3K/Akt/mTOR in this disease condition.

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Authors and Affiliations

  1. Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L’Aquila, L’Aquila, Italy

    Giovanni Luca Gravina, Andrea Mancini, Luca Scarsella, Alessandro Colapietro, Ana Jitariuc, Flora Vitale, Francesco Marampon & Claudio Festuccia

  2. Department of Biotechnological and Applied Clinical Sciences, Division of Radiation Oncology, University of L’Aquila, L’Aquila, Italy

    Giovanni Luca Gravina

  3. Department of Biotechnological and Applied Clinical Sciences, Division of Medical Oncology, University of L’Aquila, L’Aquila, Italy

    Enrico Ricevuto

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  1. Giovanni Luca Gravina
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Correspondence to Claudio Festuccia.

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Gravina, G.L., Mancini, A., Scarsella, L. et al. Dual PI3K/mTOR inhibitor, XL765 (SAR245409), shows superior effects to sole PI3K [XL147 (SAR245408)] or mTOR [rapamycin] inhibition in prostate cancer cell models. Tumor Biol. 37, 341–351 (2016). https://doi.org/10.1007/s13277-015-3725-3

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  • DOI: https://doi.org/10.1007/s13277-015-3725-3

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