Tumor Microenvironment Modulates Invadopodia Activity of Non-Selected and Acid-Selected Pancreatic Cancer Cells and Its Sensitivity to Gemcitabine and C18-Gemcitabine
Tiago M. A. Carvalho,
Madelaine Magalì Audero,
Maria Raffaella Greco,
Marilena Ardone,
Teresa Maggi,
Rosanna Mallamaci,
Barbara Rolando,
Silvia Arpicco,
Federico Alessandro Ruffinatti,
Alessandra Fiorio Pla,
Natalia Prevarskaya,
Tomas Koltai,
Stephan J. Reshkin,
Rosa Angela Cardone
Affiliations
Tiago M. A. Carvalho
Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
Madelaine Magalì Audero
U1003 PHYCEL Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, 59000 Lille, France
Maria Raffaella Greco
Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
Marilena Ardone
Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
Teresa Maggi
Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
Rosanna Mallamaci
Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
Barbara Rolando
Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
Silvia Arpicco
Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
Federico Alessandro Ruffinatti
Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
Alessandra Fiorio Pla
U1003 PHYCEL Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, 59000 Lille, France
Natalia Prevarskaya
U1003 PHYCEL Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, 59000 Lille, France
Tomas Koltai
Hospital del Centro Gallego de Buenos Aires, Buenos Aires 2199, Argentina
Stephan J. Reshkin
Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
Rosa Angela Cardone
Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy
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: 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. 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: We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.
