SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance  

作　　者：Ornella Randazzo Stella M.Cascioferro Camilla Pecoraro Widad Ait Iddouch Amir Avan Barbara Parrino Daniela Carbone Ugo Perricone Godefridus J.Peters Patrizia Diana Elisa Giovannetti 

机构地区：[1]Department of Medical Oncology,Cancer Center Amsterdam,Amsterdam UMC,VU University Medical Center,Amsterdam 1081 HV,The Netherlands [2]Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche(STEBICEF),Universitàdegli Studi di Palermo,Palermo 90133,Italy [3]Metabolic Syndrome Research Center,Mashhad University of Medical Sciences,Mashhad 91886-17871,Iran [4]Cancer Research Center,Mashhad University of Medical Sciences,Mashhad 91886-17871,Iran [5]Student Research Committee,School of Medicine,Mashhad University of Medical Sciences,Mashhad 91886-17871,Iran [6]Drug Discovery Unit,Fondazione Ri.MED,Palermo 90128,Italy [7]Department of Biochemistry,Medical University of Gdansk,Gdansk 80-210,Poland [8]Cancer Pharmacology Lab,AIRC Start Up Unit,Fondazione Pisana per la Scienza,Pisa 56124,Italy.

出　　处：《Cancer Drug Resistance》2021年第4期904-922,共19页癌症耐药（英文）

基　　金：This work was supported by Cancer Center Amsterdam(CCA)Foundation grants 2015 and 2018;Italian 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.

摘　　要：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.

关 键 词：Pancreatic ductal adenocarcinoma GEMCITABINE indole derivatives anti-proliferative activity anti-migratory activity SF3B1 RON hENT1 

分 类 号：R73[医药卫生—肿瘤]