%0 Journal Article
%T Tumor Microenvironment Modulates Invadopodia Activity of Non-Selected and Acid-Selected Pancreatic Cancer Cells and Its Sensitivity to Gemcitabine and C18-Gemcitabine.
%A Carvalho TMA
%A Audero MM
%A Greco MR
%A Ardone M
%A Maggi T
%A Mallamaci R
%A Rolando B
%A Arpicco S
%A Ruffinatti FA
%A Pla AF
%A Prevarskaya N
%A Koltai T
%A Reshkin SJ
%A Cardone RA
%J Cells
%V 13
%N 9
%D 2024 Apr 23
%M 38727266
%F 7.666
%R 10.3390/cells13090730
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>For this, two PDAC cell lines, PANC-1 and Mia PaCa-2 were adapted to pHe 6.6 or not for 1 month, grown as 3D organotypic cultures and exposed to either GEM or C18 in the presence and absence of acidosis and the hypoxia inducer, deferoxamine.<BR><B>RESULTS: </B>We found that C18 has higher cytotoxic and anti-invadopodia activity than GEM in all culture conditions and especially in acid and hypoxic environments.<BR><B>CONCLUSIONS: </B>We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.