Nobiletin and Xanthohumol Sensitize Colorectal Cancer Stem Cells to Standard Chemotherapy.
Alice TurdoAntonino GlavianoGiacomo PepeFederica CalapàStefania RaimondoMicol Eleonora FioriDaniela CarboneManuela Giovanna BasilicataVeronica Di SarnoCarmine OstacoloBarbara ParrinoStella CascioferroCamilla PecoraroSimone Di FrancoDiana BellaviaMiriam GaggianesiVeronica VeschiMelania Lo IaconoGloria GanduscioVincenzo Davide PantinaLaura Rosa MangiapaneMaria Rita BongiornoRiccardo AlessandroMatilde TodaroRuggero De MariaPatrizia DianaPietro CampigliaGiorgio StassiPublished in: Cancers (2021)
Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies.