A novel combination therapy for treating breast cancer: Preclinical proof-of-concept

Abstract

Combining the anticancer drugs at their sub optimal doses with other non-cytotoxic agents possessing potential anticancer property is a promising strategy for effective anticancer treatment with reduced toxicity. In the present investigation we have evaluated combination of anticancer drugs SAHA (Vorinostat), and MS-275, Entinostat (histone deacetylase inhibitors HDACi), with non-cytotoxic drug sildenafil (SDFL), a Phosphodiesterases 5(PDE) inhibitor in xenograft models of breast cancer. The potential efficacies of PDEi in combination with HDACi in panel of cancer cell lines treated with SAHA or MS-275 in combination with SDFL to determine their impact on cell proliferation and in in vivo activities were assessed in human breast cancer xenograft model. Here in this study we have performed in vitro assay using cancer cell lines (HCT116 - Colon, PC3- Prostrate and MDAMB231- breast) followed by the study in human breast cancer xenograft animal models. A Panel of cancer cells treated with MS-275 and SDFL have shown enhanced anti-proliferative activity of the combination resulted in additive to synergism effect than compared to that of SAHA in combination with SDFL. Further, narrowed down the study with this combination to in vivo which revealed a significant inhibition (p<0.001) of tumor growth in severe combined immuno deficient mice bearing MDAMB-231, human breast cancer xenograft treated with the combination of low doses of SDFL and MS-275. The enhanced efficacy of combination therapy clearly demonstrates synergistic pharmacodynamics drug-drug interaction between PDE and HDAC inhibitors. Taken together, current study provided preclinical proof-of-concept for the novel, distinctive and enhanced anticancer activity of PDEi