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  • Previously several genes such as cytokine Lyu and


    Previously, several genes such as cytokine (Lyu and Park, 2007), cell motility-associated genes (Schotterl et al., 2017), transforming growth factor-β (TGF-β), TGF-β receptor II which is a cell surface receptor with serine/threonine kinase activity (Jiang et al., 2014, Schotterl et al., 2017), cell cycle dependent kinase (CDK) 2 and CDK4 (Chai and Zhao, 2017, Chen et al., 2016, dela Cruz et al., 2015) have been proved to be modulated by VAE and/or its components, indicating that these genes are the targets of VAE and/or its components to explain the diverse biological activities. In our study, VAE was found to downregulate the expression and activation of Axl, which result in the inhibition of cell proliferation. Mistletoe has been known to contain various types of biologically active compounds including glycoprotein (lectin), polypeptide (viscotoxin), oligosaccharides, flavonoid, and triterpene Bryostatin 1 (Chou et al., 1999, Delebinski et al., 2012, Hostanska et al., 1995, Mueller and Anderer, 1990, Schaller et al., 1998) and many studies have focused on lectins and viscotoxin and demonstrated that these two ingredients of mistletoe are the major constituents to result in the antitcancer and immunomodulatory activities (Bussing et al., 1996, Hostanska et al., 1995, Huber et al., 2002, Lavastre et al., 2002, Mannel et al., 1991, Simon et al., 2013). So, lectins and viscotoxin seem to be the most likely compounds to target Axl, although it must be proven by additional experiments. Since the evaluation of clinical relevance of in vitro studies is very important and invaluable, we referred to some previous reports. Like the interpretation by Weissenstein et al. (2014), the serum level of VAE might not be reached as high as concentrations active in our study (≥10 µg/ml) by subcutaneous injection. However, in case of intratumoral mistletoe application in pancreatic cancer patients (Schad et al., 2014), the applied mistletoe concentrations (20–160 mg) seemed to be much higher than those used in our study (3–30 µg/ml). So, we assume that the effect of VAE on concentrations used in this study might be clinically feasible. Next, we also observed that VAE inhibited the cell proliferation of A549, H460, and H1975 cells harboring wild-type or mutant EGFR gene (Fig. 3A). Colony formation assay further showed that VAE suppressed clonogenic activity of both parental and the cisplatin/erlotinib-resistant cells, A549/CisR, H460/CisR, H460/ER and H1975/ER (Figs. 3B, 4B and D). These results indicated that VAE is effective enough to abrogate proliferation of NSCLC cells which have EGFR mutations and resistances to standard anti-cancer agents or EGFR-targeted therapy.
    Materials and methods
    Conflict of interest
    Acknowledgment This work was supported by the 2014 Yeungnam University Research grant (no. 214A480010).
    Introduction Ovarian carcinoma is the most common gynaecological cancer and a major cause of cancer-related death in women [1]. The high lethality of the disease is mainly due to late diagnosis and treatment failure. In fact, the efficacy of the standard platinum drug-based therapy of ovarian carcinoma is often limited by the occurrence of drug resistance [2], [3]. Such a phenomenon is complex and, at the cellular level, it has been associated with multiple alterations including deregulated expression of Receptor Tyrosine Kinases (RTKs), which may have a prognostic relevance [4], [5], [6]. Activation of survival pathways has been involved in cellular drug resistance both to conventional drugs and to targeted agents [5], [7], [8]. Moreover, drug resistance has been often associated with an aggressive tumor cell behaviour and an increased metastatic potential [9]. In this context, RTKs may play a role by modulating cell response to drugs as well as processes favouring cell migration and invasion. For example, the onset of alternative survival pathways after activation of RTKs has been shown to influence DNA damage repair and apoptosis [10]. Among RTKs, Axl has been shown to increase the expression of enzymes involved in the DNA damage repair through the Mitogen Activated Protein Kinase (MAPK) pathway, which, in turn, has been implicated in increased survival of ovarian carcinoma cells through the promotion of the inhibitory phosphorylation of pro-apoptotic proteins, such as Bcl-2-associated death promoter (BAD) [11], [12].