Abstract
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.
Highlights
The use of the dietary polyphenols as chemosensitizing agents to enhance the efficacy of conven‐ tional cytostatic drugs has recently gained the attention of scientists and clinicians as a plausible approach for over‐ coming the limitations of chemotherapy
Fisetin acts synergistically with paclitaxel to decrease the viability of A549 cells In the first instance, we performed mg of thiazolyl blue tetrazolium bromide (MTT) assays to determine the cytotoxicity of fisetin, paclitaxel and their combinations on the human non-small cell lung cancer A549 cells and to evaluate whether FIS and PTX present additive, synergistic, or antagonistic effects on these cells
In summary, here we demonstrate that fisetin synergizes with paclitaxel in A549 non-small lung cancer cell line at concentrations achievable in vivo
Summary
The use of the dietary polyphenols as chemosensitizing agents to enhance the efficacy of conven‐ tional cytostatic drugs has recently gained the attention of scientists and clinicians as a plausible approach for over‐ coming the limitations of chemotherapy (e.g. drug resistance and cytotoxicity). While there have been numerous drugs approved for use, they have often suffered from the limited clinical applicability due to the development of resistance by tumor cells and non-specific toxicity toward normal cells [3, 4] One such a drug, paclitaxel (PTX), a taxane plant product derived from the bark of the pacific yew tree Taxus brevifolia, has demonstrated a clinically significant activity against a broad variety of tumor types and has become a first-line treatment for NSCLC [5]. The combination therapies have proven to be more potent than monotherapy in the treatment of cancers They potentiate the therapeutic efficacy of each agent alone and/or enable the use of reduced doses of a single drug and decrease the possibility of the development of drug resistance [7, 8]
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