Combination of the FGFR4 inhibitor PD173074 and 5-fluorouracil reduces proliferation and promotes apoptosis in gastric cancer

Abstract

Abstract. Our previous findings revealed that FGFR4 may be a novel therapeutic target for gastric cancer. The aim of the present study was to explore the effects of a combination of PD173074 (PD) and 5-fluorouracil (5-Fu) on the biological behavior of gastric cancer cell lines and the relevant mechanisms involved. MKN45, a gastric cancer cell line, was treated with each single agent alone or a combination of FGF19, PD and 5-Fu. Then, a series of functional assays were performed using CCK-8 assay and flow cytometry. Western blot analysis was used to determine the expression of signaling pathway and downstream-related molecules in the MKN45 cells following the different treatments. As the concentration of PD and 5-Fu increased, the cell viability gradually decreased; the viability of the combination group was less than the viability following single administration. Western blot analysis showed that FGFR4 expression was weak in the 5-Fu-treated groups when compared with the control. PD markedly increased the apoptosis rate of MKN45 cells when compared to the control; the apoptosis rate in the cells treated with the combination of PD and 5-Fu was higher than that in the cells following single treatment. Furthermore, PD reduced the expression of p-ERK and Bcl-xl and increased caspase-3 expression. Inhibition of the activity of FGFR4 may be the main mechanisms of PD effect while 5-Fu reduced FGFR4 expression. Furthermore, the effects of the combination of 5-Fu and PD in inhibiting proliferation, increasing apoptosis and arresting cell cycle were superior to these effects following the single agent treatments, suggesting that the two drugs applied in combination may contribute to the effective treatment of gastric cancer. IntroductionGastric cancer (GC) is the fourth most common malignant tumor worldwide (1). GC patients in China have an extremely high rate of morbidity and mortality. Patients with earlystage GC account for only 20% of cases in China, which is much less than that in Japan and Korea. Therefore, most GC patients in China are diagnosed with advanced GC and require comprehensive therapy including surgery, radiotherapy and chemotherapy. Currently, there are many neoadjuvant, adjuvant and palliative chemotherapies available for GC patients, such as ECF, DCF, oxaliplatin and 5-fluorouracil (5-Fu). However, the most crucial drug is 5-Fu. Recently, targeted drugs have become an intense field in the research and application of GC treatment. Cetuximab (targeted to EGFR), bevacizumab (targeted to VEGF) and Herceptin (targeted to Her-2) have been applied in clinical trails of gastric cancer. Importantly, in October 2010, the Food and Drug Administration approved the combination of Herceptin and chemotherapy for the treatment of late-stage or metastatic GC patients with positive expression of Her-2.However, to date, no other targeted drugs have achieved a breakthrough in the treatment of GC apart for Herceptin. Although targeted drug treatment is the future direction, exploring new therapeutic targets in GC has beco...

TC-1 Overexpression Promotes Cell Proliferation in Human Non-Small Cell Lung Cancer that Can Be Inhibited by PD173074

“…This result was consistent with the previous research and suggests that the inhibition of TC-1-induced proliferation by PD173074 may provide a powerful therapeutic strategy for NSCLC treatment in a clinical setting (at least by improve the chemotherapeutic effect of cisplatin in NSCLC patient with TC-1 overexpression). Of course, further studies need to be performed in the future to confirm our results, including the exact mechanisms of TC-1, PD173074 and the relationships between TC-1 and the FGFR family, which has been demonstrated to be susceptible to the inhibitor [14], [16]–[23].…”

“…PD173074, a small-molecular-weight pharmacological tyrosine kinase inhibitor [15], has reportedly shown powerful inhibitory effects on cell proliferation [12], [14], [16]–[21]. In breast cancer, PD173074 treatment markedly reduces proliferation and promotes apoptosis in MKN45 cells.…”

“…In breast cancer, PD173074 treatment markedly reduces proliferation and promotes apoptosis in MKN45 cells. Moreover, the effects of the combination of PD173074 and 5-fluorouracil in inhibiting proliferation, increasing apoptosis were superior to these effects following the single agent treatments [16]. Sara A. Byron et al showed that treatment with PD173074 results in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2 [17].…”

FGFR4 Is a Potential Predictive Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma

“…In chemoradiotherapy-resistant cancer cells, FGFR4 protein regulates antiapoptotic signaling pathways. For instance, FGFR4 protein activates the Bcl-xl antiapoptotic signaling pathway through MAPK and regulates the antiapoptotic c-FLIP protein through the STAT3 transcription factor [37,38,39]. Similar to chemotherapy, cancer cells develop resistance to radiotherapy by acquiring antiapoptotic traits through hypoxia [40].…”

Upregulation of Fibroblast Growth Factor 19 Is Associated with the Initiation of Colorectal Adenoma

“…Increased expression of FGF19 is associated with the pathogenesis of malignant neoplasms, including leukemias and sarcomas, as well as stomach, pancreas, bladder, colon, breast, and prostate cancers [20][21][22][23][24][25][26]. Moreover, FGF19 is a potent metabolic regulator that influences energy metabolism, bile acid homeostasis and glucose/lipid homeostasis by binding to FGF receptor 4 (FGFR4) [27,28].…”