chrysin and Melanoma

Despite the progress made in treatments, melanoma is one of the cancers for which its incidence and mortality have increased during recent decades. In the research of new therapeutic strategies, natural polyphenols such as chrysin could be good candidates owing to their capacities to modulate the different fundamental aspects of tumorigenesis and resistance mechanisms, such as oxidative stress and neoangiogenesis. In the present study, we sought to determine whether chrysin could exert antitumoral effects via the modulation of angiogenesis by acting on oxidative stress and associated DNA damage. For the first time, we show a link between chrysin-induced antiproliferative effects, the activation of the DNA damage pathway, and its ability to limit angiogenesis. More specifically, herein, we show that chrysin induces single- and double-stranded DNA breaks via the activation of the DNA damage response pathway: ATM (ataxia-telangiectasia-mutated)/Chk2 (checkpoint kinase 2) and ATR (ataxia telangiectasia and Rad3-related)/Chk1 (checkpoint kinase 1) pathways. Strong activation of this DNA damage response was found to be partly involved in the ability of chrysin to limit angiogenesis and may partly involve a direct interaction between the polyphenol and DNA G-quadruplex structures responsible for the replication fork collapse. Moreover, these events were associated with a marked reduction in melanoma cells' capacity to secrete proangiogenic factor VEGF-A. The disruption of these key protein actors in tumor growth by chrysin was also confirmed in a syngeneic model of B16 melanoma. This last point is of importance to further consider the use of chrysin as a new therapeutic strategy in melanoma treatment.

Topics: Ataxia Telangiectasia Mutated Proteins; DNA Damage; Humans; Melanoma; Oxidative Stress

Numerous evidences have shown that chrysin induced cytotoxic effects via induced cell cycle arrest and induction of cell apoptosis in human cancer cell lines, however, no information showed that chrysin inhibited skin cancer cell migration and invasion. In this study, we investigated anti-metastasis mechanisms of chrysin in human melanoma cancer A375.S2 cells in vitro. Under sub-lethal concentrations of chrysin (0, 5, 10, and 15 μM) which inhibits cell mobility, migration and invasion of A375.S2 cells that were assayed by wound healing and Transwell filter. That chrysin inhibited MMP-2 activity in A375.S2 cells was investigated by gelatin zymography assay. Western blotting was used to examine protein expression and results indicated that chrysin inhibited the expression of GRB2, SOS-1, PKC, p-AKT (Thr308), NF-κBp65, and NF-κBp50 at 24 and 48 hours treatment, but only at 10-15 μM of chrysin decreased Ras, PI3K, p-c-Jun, and Snail only at 48 hours treatment and only decrease p-AKT(Ser473) at 24 hours treatment. Furthermore, chrysin (5-15 μM) decreased the expression of uPA, N-cadherin and MMP-1 at 24 and 48 hours treatment but only decreased MMP-2 and VEGF at 48 hours treatment at 10-15 μM and 5-15 μM of chrysin, respectively, however, increased E-cadherin at 5-15 μM treatment. Results of confocal laser microscopy systems indicated that chrysin inhibited expression of NF-κBp65 in A375.S2 cells. Based on these observations, we suggest that chrysin can be used in anti-metastasis of human melanoma cells in the future.

Topics: Apoptosis; Cell Culture Techniques; Cell Line, Tumor; Cell Movement; Cell Survival; Flavonoids; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Melanoma; Neoplasm Invasiveness; NF-kappa B; Skin Neoplasms

Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound extracted from honey, plants and propolis. It possesses anti-inflammatory activity, anti-oxidant properties and promotes cell death by perturbing cell cycle progression. In this study, our attention focused on the possible role that chrysin may have as a potential anti-cancer agent, and we tested its biological activity in murine and human melanoma cell lines (B16-F1 and A375). This study demonstrated that chrysin reduced melanoma cell proliferation and induced cell differentiation in both human and murine melanoma cells through synthesis increase and intracellular accumulation of protoporphirin IX (PpIX). Furthermore, following treatments with chrysin an increase in the expression of porphobilinogen deaminase (PBG-D) was noted. This study demontrated also that chrysin induces cell death in human and murine melanoma cells through caspase-dependent mechanisms, involving down-regulation of ERK 1/2, and activation of p38 MAP kinases. Induction of cell death may be a promising therapeutic approach in cancer therapy. Our results suggest that chrysin may be considered a potential candidate for both cancer prevention and treatment.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspases; Enzyme Activation; Flavonoids; Humans; Melanoma; Mice; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Tumor Cells, Cultured

Honey has long been used in medicine for different purposes. Only recently, however, its antioxidant property and preventive effects against different diseases, such as cancer, have been highlighted. Chrysin (5,7-dihydroxyflavone) is a natural flavone commonly found in acacia honey. It has previously been shown to be an anti-tumor agent. In this study, we investigated the antiproliferative role of honey or chrysin on human (A375) and murine (B16-F1) melanoma cell lines. The results of the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and the trypan blue exclusion test showed that both the tested compounds were able to induce an antiproliferative effect on melanoma cells in a dose- and time-dependent manner. Flow cytometry analysis indicated that cytotoxicity induced by honey or chrysin was mediated by G(0)/G(1) cell cycle arrest and induction of hyperploid progression. Our results suggest that the anti-proliferative effects of honey are due mainly to the presence of chrysin. Chrysin may therefore be considered a potential candidate for both cancer prevention and treatment. Further investigation is needed to validate the contribution of chrysin in tumor therapy in vivo.

Topics: Acacia; Animals; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Energy Metabolism; Flavonoids; Honey; Humans; Melanoma; Melanoma, Experimental; Mice; Time Factors