NZ51, a ring-expanded nucleoside analog, inhibits motility and viability of breast cancer cells by targeting the RNA helicase DDX3

Oncotarget
Min XieVenu Raman

Abstract

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 perm...Continue Reading

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Citations

Nov 7, 2015·Molecular Cancer·Guus Martinus BolVenu Raman
Dec 22, 2016·Clinical & Experimental Metastasis·Marise R Heerma van VossUNKNOWN Dutch Distant Breast Cancer Metastases Consortium
Jun 27, 2018·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Runjhun TandonKamaldeep Paul
Nov 7, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Annalaura BraiMaurizio Botta
Feb 28, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Marina K KukhanovaAlexander V Ivanov
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Mar 2, 2021·Medicinal Research Reviews·Yohan MalkiNicolas Masurier
Dec 6, 2017·Biochemical and Biophysical Research Communications·Zhong WangQuan-Gen Gao

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Methods Mentioned

BETA
xenografts
Flow cytometry
xenograft

Software Mentioned

Elements F
Autodock Vina
FlowJo
Exelis
Autodock
NIS
Amira

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