Therapeutic Potential of Chemically Modified, Synthetic, Triplex Peptide Nucleic Acid-Based Oncomir Inhibitors for Cancer Therapy.

ABSTRACT: miRNA-155 (miR-155) is overexpressed in various types of lymphomas and leukemias, suggesting that targeting miR-155 could be a potential platform for the development of precision medicine. Here, we tested the anticancer activity of novel, chemically modified, triplex peptide nucleic acid (PNA)-based antimiRs compared with the current state-of-the-art conventional full-length antimiRs. Next-generation modified PNAs that bound miR-155 by Watson-Crick and Hoogsteen domains possessed superior therapeutic efficacy in vivo and ex vivo compared with conventional full-length anti-miR-155. The efficacy of anti-miR-155 targeting in multiple lymphoma cell lines was comprehensively corroborated by gene expression, Western blot analysis, and cell viability-based functional studies. Finally, preclinical testing in vivo in xenograft mouse models containing lymphoma cell lines demonstrated that treatment with the miR-155-targeting next-generation antimiR resulted in a significant decrease in miR-155 expression, followed by reduced tumor growth. These findings support the effective therapeutic application of chemically modified triplex PNAs to target miR-155 to treat lymphoma. Overall, the present proof-of-concept study further implicates the potential for next-generation triplex gamma PNAs to target other miRNAs for treating cancer. SIGNIFICANCE: This study demonstrates the utility of novel oncomiR inhibitors as cancer therapeutics, providing a new approach for targeting miRNAs and other noncoding RNAs.

SUBMITTER: Dhuri K 

PROVIDER: S-EPMC8595710 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature