Aim:Because mutations of splicing factor 3B subunit-1(SF3B1)have been identified in 4%of pancreatic ductal adenocarcinoma(PDAC)patients,we investigated the activity of new potential inhibitors of SF3B1 in combination ...Aim:Because mutations of splicing factor 3B subunit-1(SF3B1)have been identified in 4%of pancreatic ductal adenocarcinoma(PDAC)patients,we investigated the activity of new potential inhibitors of SF3B1 in combination with gemcitabine,one of the standard drugs,in PDAC cell lines.Methods:One imidazo[2,1-b][1,3,4]thiadiazole derivative(IS1)and three indole derivatives(IS2,IS3 and IS4),selected by virtual screening from an in-house library,were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2,Hs766t and Panc05.04,the latter harbouring the SF3B1 mutations.The effects on the splicing pattern of proto-oncogene recepteur d’origine nantais(RON)and the gemcitabine transporter human equilibrative nucleoside transporter-1(hENT1)were assessed by PCR,while the ability to reduce tumour volume was tested in spheroids of primary PDAC cells.Results:The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell death.All compounds showed an interesting anti-migratory ability,associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h exposure.Moreover,IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures,and these results might be explained by the statistically significant increase in hENT1 expression(P<0.05 vs.untreated control cells),potentially reversing PDAC chemoresistance.Conclusion:These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.展开更多
基金This work was supported by Cancer Center Amsterdam(CCA)Foundation grants 2015 and 2018Italian Association for Cancer Research(AIRC)IG grant to Giovannetti E,European Union 2014-2020 PON Ricerca e Innovazione grant from the Italian Ministry of Education,University and Research,entitled“PROGEMA-Processi Green per l’Estrazione di Principi Attivi e la Depurazione di Matrici di Scarto e Non”(ARS01_00432)to Diana P.
文摘Aim:Because mutations of splicing factor 3B subunit-1(SF3B1)have been identified in 4%of pancreatic ductal adenocarcinoma(PDAC)patients,we investigated the activity of new potential inhibitors of SF3B1 in combination with gemcitabine,one of the standard drugs,in PDAC cell lines.Methods:One imidazo[2,1-b][1,3,4]thiadiazole derivative(IS1)and three indole derivatives(IS2,IS3 and IS4),selected by virtual screening from an in-house library,were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2,Hs766t and Panc05.04,the latter harbouring the SF3B1 mutations.The effects on the splicing pattern of proto-oncogene recepteur d’origine nantais(RON)and the gemcitabine transporter human equilibrative nucleoside transporter-1(hENT1)were assessed by PCR,while the ability to reduce tumour volume was tested in spheroids of primary PDAC cells.Results:The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell death.All compounds showed an interesting anti-migratory ability,associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h exposure.Moreover,IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures,and these results might be explained by the statistically significant increase in hENT1 expression(P<0.05 vs.untreated control cells),potentially reversing PDAC chemoresistance.Conclusion:These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.
