Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

// Giovanni Luca Gravina 1, 2 , Andrea Mancini 1 , Alessandro Colapietro 1 , Francesco Marampon 1 , Roberta Sferra 3 , Simona Pompili 3 , Leda Assunta Biordi 4 , Roberto Iorio 5 , Vincenzo Flati 4 , Christian Argueta 6 , Yosef Landesman 6 , Michael Kauffman 6 , Sharon Shacham 6 and Claudio Festuccia 1 1 Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L’Aquila, L’Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, Division of Radiotherapy, University of L’Aquila, L’Aquila, Italy 3 Department of Biotechnological and Applied Clinical Sciences, Division of Human Anatomy, University of L’Aquila, L’Aquila, Italy 4 Department of Biotechnological and Applied Clinical Sciences, Division of Molecular Pathology, University of L’Aquila, L’Aquila, Italy 5 Department of Biotechnological and Applied Clinical Sciences, Division of Applied Biology, University of L’Aquila, L’Aquila, Italy 6 Karyopharm Therapeutics, Newton, MA, USA Correspondence to: Claudio Festuccia, email: claudio.festuccia@univaq.it Keywords: castration resistant prostate cancer (CrPCa); chromosome region maintenance (CRM-1); exportin-1 (XPO-1); selective inhibitors of nuclear export (SINE); docetaxel (DTX) Received: June 29, 2017 Accepted: November 13, 2017 Published: November 30, 2017 ABSTRACT Background and aims: Docetaxel (DTX) modestly increases patient survival of metastatic castration-resistant prostate cancer (mCRPC) due to insurgence of pharmacological resistance. Deregulation of Chromosome Region Maintenance (CRM-1)/ exportin-1 (XPO-1)-mediated nuclear export may play a crucial role in this phenomenon. Material and methods: Here, we evaluated the effects of two Selective Inhibitor of Nuclear Export (SINE) compounds, selinexor (KPT-330) and KPT-251, in association with DTX by using 22rv1, PC3 and DU145 cell lines with their. DTX resistant derivatives. Results and conclusions: We show that DTX resistance may involve overexpression of β-III tubulin (TUBB3) and P-glycoprotein as well as increased cytoplasmic accumulation of Foxo3a. Increased levels of XPO-1 were also observed in DTX resistant cells suggesting that SINE compounds may modulate DTX effectiveness in sensitive cells as well as restore the sensitivity to DTX in resistant ones. Pretreatment with SINE compounds, indeed, sensitized to DTX through increased tumor shrinkage and apoptosis by preventing DTX-induced cell cycle arrest. Basally SINE compounds induce FOXO3a activation and nuclear accumulation increasing the expression of FOXO-responsive genes including p21, p27 and Bim causing cell cycle arrest. SINE compounds-catenin and survivin supporting apoptosis. βdown-regulated Cyclin D1, c-myc, Nuclear sequestration of p-Foxo3a was able to reduce ABCB1 and TUBB3 H2AX levels, prolonged γ expression. Selinexor treatment increased DTX-mediated double strand breaks (DSB), and reduced the levels of DNA repairing proteins including DNA PKc and Topo2A. Our results provide supportive evidence for the therapeutic use of SINE compounds in combination with DTX suggesting their clinical use in mCRPC patients.