1. Polymethoxyflavones from Gardenia oudiepe (Rubiaceae) induce cytoskeleton disruption-mediated apoptosis and sensitize BRAF-mutated melanoma cells to chemotherapy.
- Author
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Gonçalves de Oliveira-Júnior R, Marcoult-Fréville N, Prunier G, Beaugeard L, Beserra de Alencar Filho E, Simões Mourão ED, Michel S, Quintans-Júnior LJ, Guedes da Silva Almeida JR, Grougnet R, and Picot L
- Subjects
- Antineoplastic Agents pharmacology, Caspase 3 metabolism, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Cytoskeleton metabolism, Drug Synergism, Enzyme Activation drug effects, Flavones chemistry, Flavones metabolism, Humans, Molecular Docking Simulation, Protein Conformation, Structure-Activity Relationship, Tubulin chemistry, Tubulin metabolism, Apoptosis drug effects, Cytoskeleton drug effects, Flavones pharmacology, Gardenia chemistry, Melanoma pathology, Mutation, Proto-Oncogene Proteins B-raf genetics
- Abstract
A series of 10 natural and semisynthetic flavonoids (1 to 10) were obtained from Gardenia oudiepe (Rubiaceae), an endemic plant from New Caledonia. Most of them were polymethoxylated flavones (PMFs) of rare occurrence. After a cell viability screening test, PMFs 2 and 3 showed significant cytotoxic activity against A2058 human melanoma cells (IC
50 = 3.92 and 8.18 μM, respectively) and were selected for in-depth pharmacological assays. Both compounds inhibited cell migration and induced apoptosis and cell cycle arrest after 72h of treatment. Immunofluorescence assays indicated that these outcomes were possibly related to the induction of cytoskeleton disruption associated to actin and tubulin depolymerization. These data were confirmed by molecular docking studies, which showed a good interaction between PMFs 2 and 3 and tubulin, particularly at the colchicine binding site. As A2058 are considered as chemoresistant to conventional chemotherapy, compounds 2 and 3 (½IC50 ) were associated to clinically-used antimelanoma drugs (vemurafenib and dacarbazine) and combined therapies efficacy was assessed by the MTT assay. PMFs 2 restored the sensitivity of A2058 cells to dacarbazine treatment (IC50 = 49.38 μM vs. >100 μM). Taken together, these data suggest that PMFs from G. oudiepe could be potential leaders for the design of new antimelanoma drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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