Can the phenolic compounds of Manuka honey chemosensitize colon cancer stem cells? A deep insight into the effect on chemoresistance and self-renewal
Danila Cianciosi, Yasmany Armas Díaz, José M. Álvarez-Suárez, Xiumin Chen, Di Zhang, Nohora Milena Martínez López, Mercedes Briones Urbano, José L. Quiles, Adolfo Amici, Maurizio Battino, Francesca Giampieri
Abstract
Manuka honey, which is rich in pinocembrin, quercetin, naringenin, salicylic, p-coumaric, ferulic, syringic and 3,4-dihydroxybenzoic acids, has been shown to have pleiotropic effects against colon cancer cells. In this study, potential chemosensitizing effects of Manuka honey against 5-Fluorouracil were investigated in colonspheres enriched with cancer stem cells (CSCs), which are responsible for chemoresistance. Results showed that 5-Fluorouracil increased when it was combined with Manuka honey by downregulating the gene expression of both ATP-binding cassette sub-family G member 2, an efflux pump and thymidylate synthase, the main target of 5-Fluorouracil which regulates the ex novo DNA synthesis. Manuka honey was associated with decreased self-renewal ability by CSCs, regulating expression of several genes in Wnt/β-catenin, Hedgehog and Notch pathways. This preliminary study opens new areas of research into the effects of natural compounds in combination with pharmaceuticals and, potentially, increase efficacy or reduce adverse effects.