Combining anti-gene γPNA with small molecules and RNA inhibitors: A strategy to enhance anti-tumor efficacy.

Targeting genomic DNA to silence oncogenes is a promising strategy for cancer therapy. Gamma peptide nucleic acid (γPNA) targeting c-Myc genomic DNA has shown established efficacy in vitro and in multiple preclinical models. In this study, we investigated a combination treatment by integrating γPNAs with direct or indirect c-Myc inhibitors to further enhance the anti-tumor effect. Antigene γPNAs treatment combined with histone deacetylase inhibitors (HDACis) resulted in a synergistic reduction in c-Myc mRNA expression, protein levels, and cell viability in vitro. Additionally, the combination of γPNAs with MYC/MAX inhibitors reduced the IC50, thereby enhancing their anti-tumor efficacy. We also examined the co-delivery of γPNAs with small interfering RNA (siRNA), which significantly downregulated c-Myc mRNA and protein expression. Furthermore, small molecules targeting c-Myc indirectly exhibited high synergy scores. This study demonstrates that combining anti-gene γPNAs with small molecules or antisense approaches creates a potent and synergistic strategy for targeting c-Myc-driven cancers, presenting a promising therapeutic avenue for cancer treatment.