TY - JOUR

T1 - Single Shot vs. Cocktail: A Comparison of Mono- and Combinative Application of miRNA-Targeted Mesyl Oligonucleotides for Efficient Antitumor Therapy

AU - Gaponova, Svetlana

AU - Patutina, Olga

AU - Sen’kova, Aleksandra

AU - Burakova, Ekaterina

AU - Savin, Innokenty

AU - Markov, Andrey

AU - Shmendel, Elena

AU - Maslov, Mikhail

AU - Stetsenko, Dmitry

AU - Vlassov, Valentin

AU - Zenkova, Marina

N1 - Funding Information: This research was funded by the Russian Science Foundation (grant no: 19-14-00250 and 19-74-30011) and, in part, by the Ministry of Science and Higher Education of the Russian Federation (project of Novosibirsk State University no. FSUS-2020-0035, synthesis of modified oligonucleotides). Publisher Copyright: © 2022 by the authors.

PY - 2022/9

Y1 - 2022/9

N2 - Rational combinations of sequence-specific inhibitors of pro-oncogenic miRNAs can efficiently interfere with specific tumor survival pathways, offering great promise for targeted therapy of oncological diseases. Herein, we uncovered the potential of multicomponent therapy by double or triple combinations of highly potent mesyl phosphoramidate (µ) antisense oligodeoxynucleotides targeted to three proven pro-oncogenic microRNAs—miR-17, miR-21, and miR-155. A strong synergism in the inhibition of proliferation and migration of B16 melanoma cells was demonstrated in vitro for pairs of µ-oligonucleotides, which resulted in vivo in profound inhibition (up to 85%) of lung metastases development after intravenous injection of µ-oligonucleotide-transfected B16 cells in mice. A clear benefit of µ-21-ON/µ-17-ON and µ-17-ON/µ-155-ON/µ-21-ON combination antitumor therapy was shown for the lymphosarcoma RLS40 solid tumor model. In vivo administration of the µ-17-ON/µ-155-ON/µ-21-ON cocktail into RLS40-bearing mice elicited fourfold delay of tumor growth as a result of strong inhibition of tumor mitotic activity. It was discovered that the cocktail of µ-21-ON/µ-17-ON/µ-155-ON led to a twofold decrease in total destructive changes in murine liver, which indicates both the reduction in toxic tumor burden and the absence of specific toxicity of the proposed therapy.

AB - Rational combinations of sequence-specific inhibitors of pro-oncogenic miRNAs can efficiently interfere with specific tumor survival pathways, offering great promise for targeted therapy of oncological diseases. Herein, we uncovered the potential of multicomponent therapy by double or triple combinations of highly potent mesyl phosphoramidate (µ) antisense oligodeoxynucleotides targeted to three proven pro-oncogenic microRNAs—miR-17, miR-21, and miR-155. A strong synergism in the inhibition of proliferation and migration of B16 melanoma cells was demonstrated in vitro for pairs of µ-oligonucleotides, which resulted in vivo in profound inhibition (up to 85%) of lung metastases development after intravenous injection of µ-oligonucleotide-transfected B16 cells in mice. A clear benefit of µ-21-ON/µ-17-ON and µ-17-ON/µ-155-ON/µ-21-ON combination antitumor therapy was shown for the lymphosarcoma RLS40 solid tumor model. In vivo administration of the µ-17-ON/µ-155-ON/µ-21-ON cocktail into RLS40-bearing mice elicited fourfold delay of tumor growth as a result of strong inhibition of tumor mitotic activity. It was discovered that the cocktail of µ-21-ON/µ-17-ON/µ-155-ON led to a twofold decrease in total destructive changes in murine liver, which indicates both the reduction in toxic tumor burden and the absence of specific toxicity of the proposed therapy.

KW - anti-miRNA therapy

KW - antisense oligonucleotide

KW - lymphosarcoma

KW - melanoma

KW - mesyl phosphoramidate

KW - oligonucleotide cocktail

KW - oncogenic microRNA

UR - http://www.scopus.com/inward/record.url?scp=85138727458&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/3f678809-b273-39d2-8bcf-4942b9a8409a/

U2 - 10.3390/cancers14184396

DO - 10.3390/cancers14184396

M3 - Article

C2 - 36139555

AN - SCOPUS:85138727458

VL - 14

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 18

M1 - 4396

ER -