Abstract The practice of combining multiple drugs to increase pharmacological efficacy or reduce toxicity is widely adopted in cancer chemotherapeutics. Actinomycin D (Act D) is the first FDA-approved anticancer antibiotic. However, it’s widespread application was hindered by severe dose-related toxicities. In the current study, we investigated the in vitro and in vivo anticancer efficacy of the combination of Act D with resveratrol, a natural dietary compound abundant in red grapes and wines. We found that the combination of Act D and resveratrol synergistically inhibited cancer cell growth in vitro. We also explored the underlying mechanism of this synergistic efficacy by investigating the activation of p53 pathway including the expression of p53 target genes p21, PUMA and GDF15. Consistent with the cell growth inhibition, Act D, resveratrol and their combination activated p53 and induced the expression of p21, PUMA and GDF15 mRNA and proteins. The combination had better effects than any of the single agent. Ablation of p53 expression by shRNA almost completely abolished the expression of p21, PUMA and GDF15 suggesting p53-dependent expression of these genes. Finally, we investigated the in vivo efficacy of these agents and their combination using MDA686TU (686TU) xenografts in nude mice. Although both Act D, resveratrol and their combination significantly inhibited the growth of xenografts, the combination did not have better effects when compared to single agent. The in vivo efficacy of these compounds was further supported by Ki-67 expression in tumor tissues. Taken together, our findings demonstrated that although the combination of Act D and resveratrol showed synergistic effects in vitro, the in vivo efficacy was not. Supported by P20GM103434 and R15DE032063. Citation Format: Raji M. Lukmon, Jihan F. Amin, A.R.M. Ruhul Amin. The combination of actinomycin D and resveratrol induces synergistic anticancer activities against aerodigestive tract cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3643.
Lukmon et al. (2026) studied this question.