4.7 Article

Icariside II potentiates paclitaxel-induced apoptosis in human melanoma A375 cells by inhibiting TLR4 signaling pathway

Journal

FOOD AND CHEMICAL TOXICOLOGY
Volume 50, Issue 9, Pages 3019-3024

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.fct.2012.06.027

Keywords

Icariside II; Paclitaxel; Melanoma; Apoptosis; TLR4

Funding

  1. National Basic Science Program of China [2009CB523000]
  2. National Natural Science Foundation of China [81102541]

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Combination therapy of paclitaxel (taxol) with natural anti-tumor agents that are capable of inhibiting survival signals may provide a rational molecular basis for novel chemotherapeutic strategies. Our previous study showed that icariside II (IS), derived from Herba Epimedii, inhibited the proliferation of melanoma cells in vivo and in vitro through the regulation of apoptosis. In this report, the combination effects of paclitaxel and IS were investigated in human melanoma A375 cells. As compared to the treatment with paclitaxel alone, the co-administration of IS and paclitaxel resulted in an enhancement of apoptosis as revealed by WST-8 and PI assays. Meanwhile, Western blot analysis showed that the co-administration of IS and paclitaxel resulted in increases of cleaved caspase-3, one of the terminal pro-apoptotic proteins. In melanoma, IL-8 and VEGF are positively correlated with disease stage and a high probability of progression. We demonstrated that treatment of A375 cells with IS in combination with paclitaxel resulted in a significant decrease in the production of IL-8 and VEGF, compared with paclitaxel alone. Recent studies suggest that TLR4-MyD88-ERK signaling may be a novel target for reversing chemoresistance to paclitaxel. Our flow cytometry and Western blot data showed that paclitaxel activated TLR4-MyD88-ERK signaling and that IS treatment could effectively inhibit this paclitaxel-induced activation of TLR4-MyD88-ERK signaling. In conclusion, this study demonstrated for the first time that IS could potentiate paclitaxel-induced apoptosis in melanoma cells. These effects were mediated, at least in part, by inhibiting the activation of the TLR4 signal transduction pathways. These findings support further preclinical evaluation of IS as a new potential anti-tumor agent. (C) 2012 Elsevier Ltd. All rights reserved.

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