Background The use of the dietary polyphenols as chemosensitizing agents to enhance the efficacy of conventional cytostatic drugs has recently gained the attention of scientists and clinicians as a plausible approach for overcoming the limitations of chemotherapy (e.g. drug resistance and cytotoxicity). The aim of this study was to investigate whether a naturally occurring diet-based flavonoid, fisetin, at physiologically attainable concentrations, could act synergistically with clinically achievable doses of paclitaxel to produce growth inhibitory and/or pro-death effects on A549 non-small cell lung cancer cells, and if it does, what mechanisms might be involved.MethodsThe drug–drug interactions were analyzed based on the combination index method of Chou and Talalay and the data from MTT assays. To provide some insights into the mechanism underlying the synergistic action of fisetin and paclitaxel, selected morphological, biochemical and molecular parameters were examined, including the morphology of cell nuclei and mitotic spindles, the pattern of LC3-II immunostaining, the formation of autophagic vacuoles at the electron and fluorescence microscopic level, the disruption of cell membrane asymmetry/integrity, cell cycle progression and the expression level of LC3-II, Bax, Bcl-2 and caspase-3 mRNA.ResultsHere, we reported the first experimental evidence for the existence of synergism between fisetin and paclitaxel in the in vitro model of non-small cell lung cancer. This synergism was, at least partially, ascribed to the induction of mitotic catastrophe. The switch from the cytoprotective autophagy to the autophagic cell death was also implicated in the mechanism of the synergistic action of fisetin and paclitaxel in the A549 cells. In addition, we revealed that the synergism between fisetin and paclitaxel was cell line-specific as well as that fisetin synergizes with arsenic trioxide, but not with mitoxantrone and methotrexate in the A549 cells.ConclusionsOur results provide rationale for further testing of fisetin in the combination with paclitaxel or arsenic trioxide to obtain detailed insights into the mechanism of their synergistic action as well as to evaluate their toxicity towards normal cells in an animal model in vivo. We conclude that this study is potentially interesting for the development of novel chemotherapeutic approach to non-small cell lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0288-3) contains supplementary material, which is available to authorized users.
Cultured human melanocytes are increasingly being used in the treatment of vitiligo. The growth media contain various types of mitogenic factors, both recombinant human (e.g., rhbFGF and rhSCF) and synthetic (e.g., TPA). High concentrations of mitogenic factors accelerate the cell cycle, and consequently may increase the risk of carcinogenesis of transplanted cells. Mutations of genes of the RAS/RAF/MEK/ERK signaling pathway are very often found in the early stages of the development of melanoma. TPA is considered to be an oncogenic factor, but so far there is no evidence to show that it is responsible for damage to the genetic material of cultured melanocytes. The aim of our study was to assess the risk of the development of mutations in selected genes of the RAS/RAF/MEK/ERK signaling pathway during the culturing of melanocytes in various growth media. Based on the results obtained, it can be concluded that TPA and high concentrations of other growth factors intensify the proliferation of melanocytes, without the risk of damage to the HRAS (exon 1 and 2), KRAS (exon 1 and 2), NRAS (exon 1 and 2), and BRAF (exon 11 and 15) genes. In order to assess the total safety of the transplantation of cultured melanocytes, it is necessary to carry out further studies on other signaling pathways as well as carry out biological tests on an animal model.
Oxidative stress plays an important role in the development of vitiligo. The aim of our study was to assess the effect of oral vitamin supplementation with antioxidant activity on the effectiveness of the vitiligo treatment. The study group consisted of 46 patients suffering from nonsegmental vitiligo for over a year. Before and after the therapy, the clinical advancement of the disease (VASI) and impairment of quality of life (DLQI) were assessed in all patients, and the activities of selected antioxidant enzymes (SOD, CAT, and GPx), lipid peroxidation products (MDA), and vitamins A and E were determined. Each patient was randomly assigned to one of three therapeutic groups: FOTO (UVB therapy at 311 nm, 3x a week for 4 months), WIT (oral antioxidant supplementation-vitamin A + E at a dose of 5000 IU of retinol and 400 mg of tocopherol), and FOTO + WIT (combination therapy). After the treatment, an increase in all antioxidant enzymes and a decrease in the concentration of malondialdehyde in patients were noted, regardless of the therapeutic method used. The greatest improvement in the repigmentation of skin lesions was achieved in patients treated with combined therapy (VASI −6.95 ± 4.69, p < 0.01 , DLQI −1.90 ± 2.77, p = 0.011 ). The burden of patients with risk factors for oxidative stress turned out to be associated with a greater severity of the disease process, and a longer period of disease was positively correlated with a reduction in the quality of life in patients.
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