首页|Effects of triggers of senescence and senolysis in murine pancreatic cancer cells

Effects of triggers of senescence and senolysis in murine pancreatic cancer cells

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Effects of triggers of senescence and senolysis in murine pancreatic cancer cells
Background:The combination of senescence triggers with senolytic drugs is considered a promising new approach to cancer therapy.Here,we studied the efficacy of the genotoxic agent etoposide(Eto)and irra-diation in inducing senescence of Panc02 pancreatic cancer cells,and the capability of the Bcl-2 inhibitor navitoclax(ABT-263;Nav)to trigger senolysis.Methods:Panc02 cells were treated with Eto or irradiated with 5-20 Gy before exposure to Nav.Cell survival,proliferation,and senescence were assessed by trypan blue staining,quantification of DNA syn-thesis,and staining of senescence-associated β-galactosidase(SA-β-Gal)-positive cells,respectively.Levels of mRNA were determined by real-time polymerase chain reaction,and protein expression was analyzed by immunoblotting.Panc02 cells were also grown as pancreatic tumors in mice,which were subsequently treated with Eto and Nav.Results:Eto and irradiation had an antiproliferative effect on Panc02 cells that was significantly or ten-dentially enhanced by Nav.In vivo,Eto and Nav together,but not Eto alone,significantly reduced the pro-portion of proliferating cells.The expression of the senescence marker γH2AX and tumor infiltration with T-cells were not affected by the treatment.In vitro,almost all Eto-exposed cells and a significant propor-tion of cells irradiated with 20 Gy were SA-β-Gal-positive.Application of Nav reduced the percentage of SA-β-Gal-positive cells after irradiation but not after pretreatment with Eto.In response to triggers of senescence,cultured Panc02 cells showed increased protein levels of γH2AX and the autophagy marker LC3B-Ⅱ,and higher mRNA levels of Cdkn1a,Mdm2,and PAI-1,while the effects of Nav were variable.Conclusions:In vitro and in vivo,the combination of senescence triggers with Nav inhibited tumor cell growth more effectively than the triggers alone.Our data also provide some evidence for senolytic effects of Nav in vitro.

Pancreatic cancerPanc02 cellsEtoposideIrradiationNavitoclax

Denis Revskij、Aline Woitas、Bianca K?lle、Camilla Umst?tter、Dietmar Zechner、Faiz M Khan、Georg Fuellen、Robert Jaster

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Department of Medicine Ⅱ,Division of Gastroenterology,Rostock University Medical Center,Rostock,Germany

Rudolf-Zenker-Institute of Experimental Surgery,Rostock University Medical Center,Rostock,Germany

Department of Systems Biology and Bioinformatics,Institute of Computer Science,University of Rostock,Rostock,Germany

Institute for Biostatistics and Informatics in Medicine and Ageing Research,Rostock University Medical Center,Rostock,Germany

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Pancreatic cancer Panc02 cells Etoposide Irradiation Navitoclax

2024

10.1016/j.hbpd.2024.06.001

国际肝胆胰疾病杂志(英文版)
浙江省医学学术交流管理中心,浙江大学医学院附属第一医院,浙江大学出版社有限责任公司

国际肝胆胰疾病杂志(英文版)

影响因子：0.668
ISSN：1499-3872
年,卷(期)：2024.23(6)