Small molecules baicalein and cinnamaldehyde are potentiators of measles virus-induced breast cancer oncolysis

Background: Although the breast cancer mortality has slowed down from 2008 to 2017, breast cancer incidence rate continues to rise and thus, new and/or improved treatments are highly needed. Among them, oncolytic virotherapy which has the ability of facilitating the antitumor adaptive immunity, appears as a promising anticancer therapy. Oncolytic measles virus (MV) is particularly suitable for targeting breast cancer due to the upregulation of MV's receptor nectin-4. Nonetheless, with limited clinical success currently, ways of boosting MV-induced breast cancer oncolysis are therefore necessary. Oncolytic virotherapy alone and combined with chemotherapeutic drugs are two strategic areas with intensive development for the search of anticancer drugs. Considering that baicalein (BAI) and cinnamaldehyde (CIN) have demonstrated antitumor properties against multiple cancers including breast cancer, they could be good partners for MV-based oncolytic virotherapy. Purpose: To assess the in vitro effect of BAI and CIN with MV and assess their combination effects. Methods: We examined the combinatorial cytotoxic effect of oncolytic MV and BAI or CIN on MCF-7 breast cancer cells. Potential anti-MV activities of the phytochemicals were first investigated in vitro to determine the optimal combination model. Synergism of MV and BAI or CIN was then evaluated in vitro by calculating the combination indices. Finally, cell cycle analysis and apoptosis assays were performed to confirm the mechanism of synergism. Results: Overall, the viral sensitization combination modality using oncolytic MV to first infect MCF-7 breast cancer cells followed by drug treatment with BAI or CIN was found to produce significantly enhanced tumor killing. Further mechanistic studies showed that the combinations ‘MV-BAI’ and ‘MV-CIN’ display synergistic anti-breast cancer effect, mediated by elevated apoptosis. Conclusion: We demonstrated, for the first time, effective combination of oncolytic MV with BAI or CIN that could be further explored and potentially developed into novel therapeutic strategies targeting nectin-4-marked breast cancer cells.