PURPOSE: Multidrug resistance (MDR) may develop due to a series of adaptive responses under a new stress conditions, such as chemotherapy. Novel strategies are urgently needed to fight MDR in cancer, and chemotherapeutics that are selective for MDR cancer cells offer a promising approach. Certain protoflavones were previously found to have potential in this regard. METHODS: Cytotoxicity of six protoflavones was assessed in different P-glycoprotein overexpressing MDR cancer cell lines and in their non-MDR counterparts. The impacts of compound 5, 6-methylprotoflavone previously published and a new derivative, 6-bromoprotoflavone (compound 6), on the cell cycle distribution were evaluated, and 6 was also studied for its potential to regulate the intracellular antioxidative capacity. RESULTS: Protoflavones showed a significant cytotoxicity against all cancer cell lines and selectivity toward MDR cancer cells adapted to conventional chemotherapeutics. Inverse sensitivity versus MDR selectivity pattern was observed. Treatment with H₂O₂ showed that MDR cancer cells are more vulnerable to oxidative stress. Compounds 5 and 6 significantly decreased the portion of MDR cells in the G1 phase. The levels of reactive oxygen and nitrogen species (ROS/RNS) between MDR and non-MDR cells significantly differed upon exposure to 6, accompanied by changes in the glutathione (GSH) levels and in the expression of manganese superoxide dismutase (MnSOD), glutathione-S-transferase π (GST π) and hypoxia-inducible factor-1α (HIF-1α). CONCLUSIONS: Our results suggest that MDR cancer cells can be more vulnerable to the pro-oxidative activity of protoflavones due to an impaired antioxidative defense that might arise during the adaptation processes provoked by chemotherapy.
PURPOSE: Multidrug resistance (MDR) may develop due to a series of adaptive responses under a new stress conditions, such as chemotherapy. Novel strategies are urgently needed to fight MDR in cancer, and chemotherapeutics that are selective for MDR cancer cells offer a promising approach. Certain protoflavones were previously found to have potential in this regard. METHODS:Cytotoxicity of six protoflavones was assessed in different P-glycoprotein overexpressing MDR cancer cell lines and in their non-MDR counterparts. The impacts of compound 5, 6-methylprotoflavone previously published and a new derivative, 6-bromoprotoflavone (compound 6), on the cell cycle distribution were evaluated, and 6 was also studied for its potential to regulate the intracellular antioxidative capacity. RESULTS:Protoflavones showed a significant cytotoxicity against all cancer cell lines and selectivity toward MDR cancer cells adapted to conventional chemotherapeutics. Inverse sensitivity versus MDR selectivity pattern was observed. Treatment with H₂O₂ showed that MDR cancer cells are more vulnerable to oxidative stress. Compounds 5 and 6 significantly decreased the portion of MDR cells in the G1 phase. The levels of reactive oxygen and nitrogen species (ROS/RNS) between MDR and non-MDR cells significantly differed upon exposure to 6, accompanied by changes in the glutathione (GSH) levels and in the expression of manganese superoxide dismutase (MnSOD), glutathione-S-transferase π (GST π) and hypoxia-inducible factor-1α (HIF-1α). CONCLUSIONS: Our results suggest that MDR cancer cells can be more vulnerable to the pro-oxidative activity of protoflavones due to an impaired antioxidative defense that might arise during the adaptation processes provoked by chemotherapy.
Authors: Máté Vágvölgyi; Gábor Girst; Norbert Kúsz; Sándor B Ötvös; Ferenc Fülöp; Judit Hohmann; Jean-Yves Servais; Carole Seguin-Devaux; Fang-Rong Chang; Michael S Chen; Li-Kwan Chang; Attila Hunyadi Journal: Int J Mol Sci Date: 2019-12-12 Impact factor: 5.923