Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:6393-6395.

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

Giovanni Luca Gravina, Andrea Mancini, Alessandro Colapietro, Francesco Marampon, Roberta Sferra, Simona Pompili, Leda Assunta Biordi, Roberto Iorio, Vincenzo Flati, Christian Argueta, Yosef Landesman, Michael Kauffman, Sharon Shacham and Claudio Festuccia _

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:111225-111245. https://doi.org/10.18632/oncotarget.22760

Metrics: PDF 807 views  |   HTML 1466 views  |   ?  


Abstract

Giovanni Luca Gravina1,2, Andrea Mancini1, Alessandro Colapietro1, Francesco Marampon1, Roberta Sferra3, Simona Pompili3, Leda Assunta Biordi4, Roberto Iorio5, Vincenzo Flati4, Christian Argueta6, Yosef Landesman6, Michael Kauffman6, Sharon Shacham6 and Claudio Festuccia1

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

2Department of Biotechnological and Applied Clinical Sciences, Division of Radiotherapy, University of L’Aquila, L’Aquila, Italy

3Department of Biotechnological and Applied Clinical Sciences, Division of Human Anatomy, University of L’Aquila, L’Aquila, Italy

4Department of Biotechnological and Applied Clinical Sciences, Division of Molecular Pathology, University of L’Aquila, L’Aquila, Italy

5Department of Biotechnological and Applied Clinical Sciences, Division of Applied Biology, University of L’Aquila, L’Aquila, Italy

6Karyopharm 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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 22760