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.

• Authors: Karishma Dhuri, Ravinder Reddy Gaddam, Ajit Vikram, Frank J Slack, Raman Bahal
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 22 Pg. 5613-5624 (11 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34548334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• MIRN155 microRNA, human
• MicroRNAs
• Peptide Nucleic Acids

Topics

• Animals
• Apoptosis
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphoma (genetics, pathology, therapy)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs (antagonists & inhibitors, genetics)
• Peptide Nucleic Acids (chemistry, pharmacology)
• Proof of Concept Study
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays