Low-Intensity Low-Frequency Ultrasound Enhances The Chemosensitivity Of Pancreatic Cancer To Gemcitabine

Purpose:Tumor drug resistance(TDR)invariably leads to failure of chemotherapy.In addition,the currently available treatment strategies for overcoming TDR are not satisfactory,owing to limitations in terms of safety and feasibility.The aim of this study was to demonstrate whether low-intensity low-frequency ultrasound(LILFU)could improve the effect of chemotherapy and reverse TDR in gemcitabine-resistant ASPC-1(ASPC-1/GEM)cells.The investigation focused on the relationship of the LILFU-enhanced effectiveness with the adenosine triphosphate-binding cassette(ABC)transporters and the phosphatidylinositol 3 kinase/protein kinase B/nuclear factor-?B(PI3K/AKT/NF-?B)pathway.Materials and methods:The Cell Counting Kit-8 assay was applied to select the appropriate acoustic intensity and half-inhibitory concentration of gemcitabine.The ASPC-1/GEM cells were divided into a Control,GEM,LILFU,and GEM+LILFU groups.Cell proliferation was evaluated through clone formation,while cell apoptosis was detected using flow cytometry.Western blotting was used to explore the expression of ABC transporters and PI3K/AKT/NF-?B pathway-related proteins.ASPC-1/GEM xenograft mice were established to identify the enhancing effect of GEM+LILFU in vivo.Immunohistochemical staining was used to detect the expression of KI67 in tumor tissue.Results:The acoustic parameter of 0.2 W/cm~2 and gemcitabine concentration of 6.63mg/m L were used in the subsequent experiments.After treatment with GEM+LILFU,the cell viability and proliferation ability decreased,whereas the apoptotic rate increased compared with the GEM group.The levels of ABC transporters(P-glycoprotein,ABC subfamily G member 2,multidrug resistance-associated protein 1)and PI3K/AKT/NF-?B pathway-related proteins(PI3K-P110?,NF-?B)were decreased in the GEM+LILFU group.More importantly,LILFU increased the effectiveness of GEM in inhibiting tumor growth and reduced the expression of KI-67 in ASPC-1/GEM xenograft mice.Conclusion:LILFU improves the chemosensitivity of ASPC-1/GEM,by inhibiting cell viability and proliferation,and promoting cell apoptosis in the GEM+LILFU group.Our results indicate that the enhancing effect of LILFU may be attributed to the decreasing expression of ABC transporters and PI3K/AKT/NF-?B pathway-related proteins.