NZ51, a ring-expanded nucleoside analog, inhibits motility and viability of breast cancer cells by targeting the RNA helicase DDX3
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Min Xie1, Farhad Vesuna1, Mahendran Botlagunta1, Guus Martinus Bol1,2, Ashley Irving1, Yehudit Bergman1, Ramachandra S. Hosmane3, Yoshinori Kato1, Paul T. Winnard Jr.1, Venu Raman1,2,4
1Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2Department of Pathology, University Medical Center Utrecht Cancer Center, GA, Utrecht, The Netherlands
3Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, MD, USA
4Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Venu Raman, e-mail: [email protected]
Keywords: ring-expanded nucleoside, RNA helicase DDX3
Received: June 03, 2015 Accepted: July 29, 2015 Published: August 11, 2015
DDX3X (DDX3), a human RNA helicase, is over expressed in multiple breast cancer cell lines and its expression levels are directly correlated to cellular aggressiveness. NZ51, a ring-expanded nucleoside analogue (REN) has been reported to inhibit the ATP dependent helicase activity of DDX3. Molecular modeling of NZ51 binding to DDX3 indicated that the 5:7-fused imidazodiazepine ring of NZ51 was incorporated into the ATP binding pocket of DDX3. In this study, we investigated the anticancer properties of NZ51 in MCF-7 and MDA-MB-231 breast cancer cell lines. NZ51 treatment decreased cellular motility and cell viability of MCF-7 and MDA-MB-231 cells with IC50 values in the low micromolar range. Biological knockdown of DDX3 in MCF-7 and MDA-MB-231 cells resulted in decreased proliferation rates and reduced clonogenicity. In addition, NZ51 was effective in killing breast cancer cells under hypoxic conditions with the same potency as observed during normoxia. Mechanistic studies indicated that NZ51 did not cause DDX3 degradation, but greatly diminished its functionality. Moreover, in vivo experiments demonstrated that DDX3 knockdown by shRNA resulted in reduced tumor volume and metastasis without altering tumor vascular volume or permeability-surface area. In initial in vivo experiments, NZ51 treatment did not significantly reduce tumor volume. Further studies are needed to optimize drug formulation, dose and delivery. Continuing work will determine the in vitro-in vivo correlation of NZ51 activity and its utility in a clinical setting.
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