Mistletoe is universal name for various
Mistletoe is universal name for various species of parasitic plant which grows attached to and within the branches of host trees such as apple, elm, oak and pine. Mistletoe extract prepared from Viscum album, a species of mistletoe in the family Santalaceae, is generally known as European mistletoe and frequently prescribed to improve numerous health problems including hypertension, diabetes mellitus, inflammation, arthritis, and viral infection (Bock et al., 2014, Glickman-Simon and Pettit, 2015, Gorter et al., 1999, Kim et al., 2014, Tusenius et al., 2005). Especially, it has been steadily considered as a potent complementary and alternative medicine to treat various human solid tumors (Mansky et al., 2013, Shakeel et al., 2014, Weissenstein et al., 2016). Accumulating evidence from in vitro and in vivo studies has proposed various possible mechanisms involved in the anti-tumor activity of mistletoe extract or its biologically active components such as lectins and viscotoxins (Bussing et al., 1996, Schaller et al., 1998), which are inhibition of Lapatinib Ditosylate (dela Cruz et al., 2015), induction of apoptosis (Kovacs, 2010), degradation of cytoskeletal proteins (Lavastre et al., 2007), and alteration of expression and/or activity of intracellular molecules which transduce signals for cell growth, survival and proliferation (Lavastre et al., 2002, Lyu and Park, 2007, Ucar et al., 2012). Although the therapeutic values of mistletoe extracts keep growing, the underlying mechanisms to explain its anti-tumor activity is not fully studied.
In this study, we aimed to explore a novel target of Visucm album extract (VAE) associated with its anti-tumor effect. Our data demonstrated the inhibitory effects of VAE on Axl expression, its activation upon a ligand binding, cell viability and colony formation in NSCLC cells. To further understand the underlying mechanisms involved in anti-proliferative effect of VAE, we also examined if VAE affects some intracellular molecules related to cell cycle regulation and apoptosis.
Discussion Platinum-based regimens and the combination with second-line agents such as docetaxel, pemetrexed, or vinorelbine have been the standard chemotherapy for NSCLC (Al-Farsi and Ellis, 2014). Recent approaches to develop personalized medicine discovered the specific inhibitors targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) and other tyrosine kinases (Gazdar, 2010, Kwak et al., 2010, Natale et al., 2009). In case of tumors with driver mutations in EGFR and ALK genes, EGFR-tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib as well as ALK-inhibitor, crizotinib, are considered as first-line anti-cancer agents (Bagcchi, 2015, Kohler and Schuler, 2013). Compared to the standard chemotherapy, the targeted therapy using EGFR-TKIs or ALK inhibitors have been shown to improve progression-free survival (Bruckl et al., 2017, Chuang and Neal, 2015). However, most of patients acquire the tolerance against cisplatin and EGFR-TKIs, which is one of the vicious problems to make the successful treatment of NSCLC difficult. Axl, a member of TAM RTK family, has been reported to be involved in the acquisition of resistance against anti-cancer drugs including EGFR-TKIs. In this study, we observed the inhibitory effect of mistletoe (Visucm album) extract (VAE), an aqueous and injectable preparation on Axl expression and its activation upon ligand stimulation in NSCLC cells (Figs. 1 and 2). Interestingly, we also found that the cytotoxic effect of VAE was inversely proportional to Axl protein level, since it was attenuated or augmented by overexpression or knockdown of Axl, respectively (Fig. 3D and F). These results strongly indicate that VAE is a potent candidate as a complementary and alternative medicine or an adjuvant for treatment of cancer patients. However, the clinical evaluations of the benefit of VAE are manifold and still conflicting, since some studies reported the significant improvement of survival, tumor regression, reduction of cytotoxicity and quality of life, while others demonstrated no positive outcomes for survival, relapse, remission, and quality of life (Kienle et al., 2016).