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Introduction
Gastric cancer is one of the most prevalent malignancies in Eastern Asia and it is one of the leading causes of cancer-related deaths worldwide (1). To date, chemotherapy is still an important treatment for patients with advanced gastric cancer. However, the efficacy of chemotherapeutic agents is severely limited due to chemoresistance and adverse side effects. Evidence has shown that chemotherapy sensitivity and chemoresistance are tightly correlated with signal transduction pathways and genetic events. Recently, kinase suppressor of Ras 1 (KSR1) and its downstream extracellular signal-regulated kinase (ERK) signaling pathway have received much attention (2).
KSR1 is an essential scaffold protein of the Ras/Raf/MAPK cascade that facilitates the activation of ERK (3). Studies have shown that the expression of KSR1 is upregulated in many types of cancer and is required for cell proliferation, apoptosis and cell-cycle reinitiation (4–6). Moreover, KSR1 was confirmed to contribute to tumorigenesis through the MAPK cascade in a mouse model (7,8). In addition, a screening experiment showed that the expression of KSR1 is correlated with cancer cell sensitivity to anticancer drugs (9). Metastasis suppressor nm23-H1 was found to bind directly to KSR1 and modulate the scaffold binding patterns, therefore facilitating its degradation and decreased ERK activation, resulting in elevated tumor cell sensitivity to cancer therapeutics (10). Our previous study also showed that etoposide activated the MAPK/ERK signaling pathway, which reduced the chemotherapy sensitivity of gastric cancer cells via suppressing expression of p53 and enhancing expression of c-Myc (11). These results indicate a significant role of the KSR1-mediated ERK signaling pathway in the pathogenesis of tumors and it might be a potential therapeutic target of chemotherapy resistance. The identification of an effective agent with few adverse side effects to suppress the KSR1-mediated ERK signaling pathway may be a potential method to reverse chemotherapy resistance in gastric cancer.
Ginkgo biloba extract (EGb), a natural antioxidant, is a well-known and inexpensive herb that has been used without side effects for centuries (12). Recently, EGb has attracted considerable attention for its antitumor properties. EGb was able to induce cell apoptosis, suppress cell proliferative, migration and tumor progression of cancer (13–15). Moreover, it was reported that EGb had chemopreventive effects in cancer cells and rat models through antiproliferation, antioxidant, anti-angiogenic and apoptosis-inducing activities (15,16). Further...