Tumor Microenvironment Modulates Invadopodia Activity of Non-Selected and Acid-Selected Pancreatic Cancer Cells and Its Sensitivity to Gemcitabine and C18-Gemcitabine.
cell invasion
chemoresistance
extracellular acidosis
hypoxia
invadopodia
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
23 Apr 2024
23 Apr 2024
Historique:
received:
20
02
2024
revised:
15
04
2024
accepted:
19
04
2024
medline:
10
5
2024
pubmed:
10
5
2024
entrez:
10
5
2024
Statut:
epublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with high mortality due to early metastatic dissemination and high chemoresistance. All these factors are favored by its extracellular matrix (ECM)-rich microenvironment, which is also highly hypoxic and acidic. Gemcitabine (GEM) is still the first-line therapy in PDAC. However, it is quickly deaminated to its inactive metabolite. Several GEM prodrugs have emerged to improve its cytotoxicity. Here, we analyzed how the acidic/hypoxic tumor microenvironment (TME) affects the response of PDAC cell death and invadopodia-mediated ECM proteolysis to both GEM and its C18 prodrug. For this, two PDAC cell lines, PANC-1 and Mia PaCa-2 were adapted to pH We found that C18 has higher cytotoxic and anti-invadopodia activity than GEM in all culture conditions and especially in acid and hypoxic environments. We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.
Sections du résumé
BACKGROUND
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with high mortality due to early metastatic dissemination and high chemoresistance. All these factors are favored by its extracellular matrix (ECM)-rich microenvironment, which is also highly hypoxic and acidic. Gemcitabine (GEM) is still the first-line therapy in PDAC. However, it is quickly deaminated to its inactive metabolite. Several GEM prodrugs have emerged to improve its cytotoxicity. Here, we analyzed how the acidic/hypoxic tumor microenvironment (TME) affects the response of PDAC cell death and invadopodia-mediated ECM proteolysis to both GEM and its C18 prodrug.
METHODS
METHODS
For this, two PDAC cell lines, PANC-1 and Mia PaCa-2 were adapted to pH
RESULTS
RESULTS
We found that C18 has higher cytotoxic and anti-invadopodia activity than GEM in all culture conditions and especially in acid and hypoxic environments.
CONCLUSIONS
CONCLUSIONS
We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.
Identifiants
pubmed: 38727266
pii: cells13090730
doi: 10.3390/cells13090730
pii:
doi:
Substances chimiques
Deoxycytidine
0W860991D6
Gemcitabine
0
Prodrugs
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Marie Curie Innovative Training Program (ITN) "pH and Ion Transport in Pancreatic Cancer-pHioniC
ID : 813834; H2020-MSCA-ITN-2018
Organisme : National Center for Gene Therapy and Drugs based on RNA Technology - PNRR per la Missione 4, componente 2-investimento 1.4
ID : CN00000041
Organisme : PRIN 2022 "AdaPtiviTy"
ID : 20227YTZE3
Organisme : PRIN 2022 PNRR "PhOXyOmicGEM"
ID : P2022L5HAZ