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1دورية أكاديمية
المؤلفون: 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
المصدر: Cells, Vol 13, Iss 9, p 730 (2024)
مصطلحات موضوعية: hypoxia, cell invasion, extracellular acidosis, invadopodia, chemoresistance, Cytology, QH573-671
الوصف: 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.
وصف الملف: electronic resource
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2دورية أكاديمية
المؤلفون: Stephan J. Reshkin, Rosa Angela Cardone, Tomas Koltai
المصدر: Cells, Vol 13, Iss 7, p 602 (2024)
مصطلحات موضوعية: PDAC (pancreatic ductal adenocarcinoma), driver mutations, KRAS, personalized treatment, Cytology, QH573-671
الوصف: Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11–12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.
وصف الملف: electronic resource
النص الكامل