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

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

doi:10.18632/oncotarget.22760

Abstract

Background and aimsDocetaxel (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 methodsHere, 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 conclusionsWe 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.

Highlights

Prostate cancer (PCa) is the second leading cause of cancer-related death in males in industrialized western countries and represents a growing problem worldwide [1]
Our results provide supportive evidence for the therapeutic use of Selective Inhibitor of Nuclear Export (SINE) compounds in combination with DTX suggesting their clinical use in metastatic castration-resistant prostate cancer (mCRPC) patients
We demonstrated the possibility that acquired DTXR may be overcome by a combinatorial therapy including SINE compounds (XPO1 inhibitors) selinexor (KPT330) or KPT-251, with the DTX

Summary

Introduction

Prostate cancer (PCa) is the second leading cause of cancer-related death in males in industrialized western countries and represents a growing problem worldwide [1]. Hormone refractory/castration resistant PCa (CRPC) usually develops after an initially therapeutically efficacious treatment with anti-hormonal compounds [2]. Most patients with CRPC relapse and become resistant to DTX therapy [4,5,6,7]. Despite the high prevalence of DTX-refractory disease, little is known about the tumor biology of the DTX-resistant residual tumor cells compared with primary tumor cells. Gene expression profiling of androgen independent prostate cancer cells demonstrates complex mechanisms mediating resistance to DTX [10]. The tumorigenic potential of residual/DTX-resistant (DTXR) cancer cells may be enhanced if the cancer cells were not eradicated by chemotherapy. 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

Methods

Results

Conclusion