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Updated: Aug 28, 2025
Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Single Shot vs. Cocktail: A Comparison of Mono- and Combinative Application of miRNA-Targeted Mesyl Oligonucleotides
Svetlana Gaponova1, Olga Patutina1, Aleksandra Sen'kova1
1Institute of Chemical Biology and Fundamental Medicine SB RAS, Lavrentiev's Ave. 8, Novosibirsk 630090, Russia.
Abstract:
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.
Insights
Multicomponent therapy using antisense oligodeoxynucleotides targeting pro-oncogenic microRNAs (miRNAs) showed significant antitumor effects. Combinations of these molecules effectively inhibited tumor growth and reduced liver toxicity in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Antisense Oligonucleotide Therapy
Background:
- Pro-oncogenic microRNAs (miRNAs) play crucial roles in tumor survival pathways.
- Targeted inhibition of specific miRNAs offers a promising strategy for cancer therapy.
Purpose of the Study:
- To evaluate the therapeutic potential of multicomponent therapy using antisense oligodeoxynucleotides (µ-oligonucleotides) targeting miR-17, miR-21, and miR-155.
- To assess the efficacy and toxicity of combined µ-oligonucleotide therapy in preclinical cancer models.
Main Methods:
- In vitro studies using B16 melanoma cells to assess proliferation and migration inhibition.
- In vivo studies in mice with B16 melanoma lung metastases and RLS40 solid tumors.
- Evaluation of tumor growth delay, mitotic activity, and liver toxicity.
Main Results:
- Synergistic inhibition of proliferation and migration of B16 melanoma cells by paired µ-oligonucleotides in vitro.
- Profound inhibition (up to 85%) of lung metastases development in vivo.
- Significant delay in RLS40 tumor growth and reduced liver destructive changes with a triple µ-oligonucleotide cocktail.
Conclusions:
- Rational combinations of µ-oligonucleotides targeting pro-oncogenic miRNAs demonstrate potent antitumor activity.
- The triple combination therapy (µ-21-ON/µ-17-ON/µ-155-ON) shows significant efficacy with reduced liver toxicity.
- This approach holds promise for targeted oncological disease therapy.
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