title: Dual PI3K/mTOR inhibitor, XL765 (SAR245409), shows superior effects to sole PI3K [XL147 (SAR245408)] or mTOR [rapamycin] inhibition in prostate cancer cell models.
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.
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.|Department of Biotechnological and Applied Clinical Sciences, Division of Radiation Oncology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mancini
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Scarsella
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Colapietro
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Jitariuc
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Vitale
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marampon
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Division of Medical Oncology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Ricevuto
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy. claudio.festuccia@univaq.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011810:Quinoxalines / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D020123:Sirolimus / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C410798:AR protein, human; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D013449:Sulfonamides; C581157:XL147; C576808:XL765; C546842:MTOR protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Drug resistance; PI3K inhibitors; Prostate cancer; mTOR