Inhibition of Src tyrosine kinase reverts chemoresistance toward 5-fluorouracil in human pancreatic carcinoma cells: an involvement of epidermal growth factor receptor signaling

Abstract

Resistance to chemotherapy is believed to be a major cause of treatment failure in pancreatic cancer. Thus, it is necessary to explore alternative therapeutic modalities to overcome drug resistance in pancreatic cancer treatment. We tested the hypothesis that Src tyrosine kinase inhibition could augment the chemosensitivity of 5-fluorouracil (5-FU)-resistant human pancreatic cancer cells to 5-FU. As detected by MTT proliferation assay, propidium iodide and annexin V staining, a combination of 5-FU þ Src kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d]pyrimidine) reflected the chemotherapeutic sensitivity and restored the 5-FU-induced apoptosis in 5-FU-resistant cells. Furthermore, when small-interfering RNA approach to silence Src gene expression was applied, the degree of 5-FU-induced apoptosis was increased in all cell lines independently of the chemoresistance status. Western blotting and RT-PCR analysis revealed that the expression of thymidylate synthase (TS) was higher in 5-FU-resistant cells, however, decreased significantly after pretreatment with PP2. Furthermore, the combination of 5-FU þ PP2 decreased the 5-FU-induced activation of epidermal growth factor receptor (EGFR)-AKT pathway. Finally, PP2 in combination with 5-FU substantially decreased the in vivo tumor growth and inhibited distant metastases. Taken together, 5-FU chemoresistance can be reversed through indirect TS regulation by inhibiting Src tyrosine kinase. A potential mechanism of action of Src kinase inhibitors on 5-FU chemosensitivity might be linked to the inhibition of 5-FU-induced EGFR-AKT activation.

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

“…4B-D). Previously, it was reported that Src inhibition reverts chemoresistance to 5-FU through thymidylate synthase regulation, and the effect of Src kinase inhibition on 5-FU chemosensitivity might be accomplished by blocking 5-FU-induced EGFR-AKT activation (39). Therefore, we tested to see if the synergy between saracatinib and 5-FU observed in our study might have resulted from thymidylate synthase downregulation.…”

Effects of Src kinase inhibition induced by dasatinib in non–small cell lung cancer cell lines treated with cisplatin

“…Src kinase inhibition by means of RNA interference or specific drugs has already been shown to enhance in vitro toxicity of cancer cells to different agents (28,29), and although in the present article, for most of the responsive cell lines, the effects of the cisplatin/dasatinib combinations seemed to be additive rather than synergistic (Fig. 2), further studies both in vitro and in vivo should be addressed to clarify the nature of the interaction between these two drugs in NSCLC, similar to what recently reported in colorectal cancer model (30).…”

Differential roles of Src in transforming growth factor-ß regulation of growth arrest, epithelial-to-mesenchymal transition and cell migration in pancreatic ductal adenocarcinoma cells

“…Moreover, overexpression of activated c-Src has been reported to stimulate migration, downregulation of E-cadherin (6), and an increase in IL-8 expression and angiogenesis (7). Pharmacologic Src inhibition demonstrated significant antitumor and antimetastatic activity in an orthotopic mouse model of human PDAC (8) and reverted inherent and acquired chemoresistance in pancreatic tumor cells in vitro (9,10) and in vivo (10).…”