42- and 63-bp anti-MDR1-siRNAs bearing 2'-OMe modifications in nuclease-sensitive sites induce specific and potent gene silencing

Olga V Gvozdeva; Iiya S Dovydenko; Alya G Venyaminova; Marina A Zenkova; Valentin V Vlassov; Elena L Chernolovskaya

doi:10.1016/j.febslet.2014.02.015

42- and 63-bp anti-MDR1-siRNAs bearing 2'-OMe modifications in nuclease-sensitive sites induce specific and potent gene silencing

FEBS Lett. 2014 Mar 18;588(6):1037-43. doi: 10.1016/j.febslet.2014.02.015. Epub 2014 Feb 20.

Authors

Olga V Gvozdeva¹, Iiya S Dovydenko¹, Alya G Venyaminova¹, Marina A Zenkova¹, Valentin V Vlassov¹, Elena L Chernolovskaya²

Affiliations

¹ Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev Avenue, Novosibirsk 630090, Russia.
² Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev Avenue, Novosibirsk 630090, Russia. Electronic address: elena_ch@niboch.nsc.ru.

PMID: 24561194
DOI: 10.1016/j.febslet.2014.02.015

Abstract

DsRNAs longer than 30bp induce interferon response and global changes in gene expression profile in mammalians. 21bp siRNA and 25/27bp dsiRNA acting via RNA interference mechanism are used for specific gene silencing in this class of organisms. We designed selectively 2'-O-methyl-modified 42 and 63bp anti-MDR1-siRNAs that silence the expression of P-glycoprotein and restore the sensitivity of drug-resistant cancer cells to cytostatic more efficiently than canonical 21bp siRNAs. We also show that they act in a Dicer-independent mode and are devoid of immunostimulating properties. Our findings suggest that 42 and 63bp siRNAs could be used as potential therapeutics.

Keywords: 2′-O-methyl modification; Dicer-substrate RNAs; Interferon response; small interfering RNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Antineoplastic Agents, Phytogenic / pharmacology
Cell Line, Tumor
Cell Survival / drug effects
Drug Resistance, Neoplasm*
Gene Expression
Gene Knockdown Techniques
Humans
RNA Interference*
RNA Processing, Post-Transcriptional
RNA, Small Interfering / chemistry
RNA, Small Interfering / genetics*
RNA, Small Interfering / metabolism
Ribose / analogs & derivatives
Ribose / chemistry
Vinblastine / pharmacology

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents, Phytogenic
RNA, Small Interfering
D-2-O-methylribose
Vinblastine
Ribose