In Vitro and in Vivo Activity of a Novel Locked Nucleic Acid (LNA)-inhibitor-miR-221 Against Multiple Myeloma Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Mar 4

PMID 24586944

Citations 53

Authors

Maria Teresa Di Martino

Annamaria Gulla

Maria Eugenia Gallo Cantafio

Emanuela Altomare

Nicola Amodio

Emanuela Leone

Eugenio Morelli

Santo Giovanni Lio

Daniele Caracciolo

Marco Rossi

Niels M Frandsen

Pierosandro Tagliaferri

Pierfrancesco Tassone

Affiliations

Soon will be listed here.

Abstract

Background & Aim: The miR-221/222 cluster is upregulated in malignant plasma cells from multiple myeloma (MM) patients harboring the t(4;14) translocation. We previously reported that silencing of miR-221/222 by an antisense oligonucleotide induces anti-MM activity and upregulates canonical miR-221/222 targets. The in vivo anti-tumor activity occurred when miR-221/222 inhibitors were delivered directly into MM xenografts. The aim of the present study was to evaluate the anti-MM activity of a novel phosphorothioate modified backbone 13-mer locked nucleic acid (LNA)-Inhibitor-miR-221 (LNA-i-miR-221) specifically designed for systemic delivery.

Methods: In vitro anti-MM activity of LNA-i-miR-221 was evaluated by cell proliferation and BrdU uptake assays. In vivo studies were performed with non-obese diabetic/severe combined immunodeficient (NOD.SCID) mice bearing t(4;14) MM xenografts, which were intraperitoneally or intravenously treated with naked LNA-i-miR-221. RNA extracts from retrieved tumors were analyzed for miR-221 levels and modulation of canonical targets expression. H&E staining and immunohistochemistry were performed on retrieved tumors and mouse vital organs.

Results: In vitro, LNA-i-miR-221 exerted strong antagonistic activity against miR-221 and induced upregulation of the endogenous target p27Kip1. It had a marked anti-proliferative effect on t(4;14)-translocated MM cells but not on MM cells not carrying the translocation and not overexpressing miR-221. In vivo, systemic treatment with LNA-i-miR-221 triggered significant anti-tumor activity against t(4;14) MM xenografts; it also induced miR-221 downregulation, upregulated p27Kip1 and reduced Ki-67. No behavioral changes or organ-related toxicity were observed in mice as a consequence of treatments.

Conclusions: LNA-i-miR-221 is a highly stable, effective agent against t(4;14) MM cells, and is suitable for systemic use. These data provide the rationale for the clinical development of LNA-i-miR-221 for the treatment of MM.

Citing Articles

Scaling approaches for the prediction of human clearance of LNA-i-mir-221: A retrospective validation.

Fonsi M, Fulbert J, Billat P, Arbitrio M, Tagliaferri P, Tassone P Curr Res Pharmacol Drug Discov. 2024; 7:100197.

PMID: 39188553 PMC: 11345919. DOI: 10.1016/j.crphar.2024.100197.

A systematic review of non-coding RNA therapeutics in early clinical trials: a new perspective against cancer.

Grillone K, Carida G, Luciano F, Cordua A, Di Martino M, Tagliaferri P J Transl Med. 2024; 22(1):731.

PMID: 39103911 PMC: 11301835. DOI: 10.1186/s12967-024-05554-4.

LNA-i-miR-221 activity in colorectal cancer: A reverse translational investigation.

Ali A, Grillone K, Ascrizzi S, Carida G, Fiorillo L, Ciliberto D Mol Ther Nucleic Acids. 2024; 35(2):102221.

PMID: 38868363 PMC: 11168481. DOI: 10.1016/j.omtn.2024.102221.

Safety and activity of the first-in-class locked nucleic acid (LNA) miR-221 selective inhibitor in refractory advanced cancer patients: a first-in-human, phase 1, open-label, dose-escalation study.

Tassone P, Di Martino M, Arbitrio M, Fiorillo L, Staropoli N, Ciliberto D J Hematol Oncol. 2023; 16(1):68.

PMID: 37365583 PMC: 10294514. DOI: 10.1186/s13045-023-01468-8.

Thyclotides, tetrahydrofuran-modified peptide nucleic acids that efficiently penetrate cells and inhibit microRNA-21.

Clausse V, Zheng H, Amarasekara H, Kruhlak M, Appella D Nucleic Acids Res. 2022; 50(19):10839-10856.

PMID: 36215040 PMC: 9638920. DOI: 10.1093/nar/gkac864.

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