PDF(Pubmed)
Abstract：
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.
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.
摘要：
背景：胰腺导管腺癌（PDAC）是一种致命的疾病，由于早期转移播散和高化学耐药性而具有高死亡率。所有这些因素都受到其富含细胞外基质（ECM）的微环境的青睐，它也是高度缺氧和酸性的。吉西他滨（GEM）仍然是PDAC的一线疗法。然而,它迅速脱去氨基为其无活性的代谢产物。已经出现了几种GEM前药以改善其细胞毒性。这里,我们分析了酸性/低氧肿瘤微环境(TME)如何影响PDAC细胞死亡和侵袭足病介导的ECM蛋白水解对GEM及其C18前药的反应.
方法：为此，两个PDAC细胞系，PANC-1和MiaPaCa-2适应pH6.6或不适应1个月，生长为3D器官型培养物，并在存在和不存在酸中毒和缺氧诱导剂的情况下暴露于GEM或C18，去铁胺.
结果：我们发现，在所有培养条件下，尤其是在酸性和低氧环境中，C18均比GEM具有更高的细胞毒性和抗invadopodia活性。
结论：我们建议C18作为一种更有效的方法来开发克服PDAC化学耐药的新治疗策略。
方法：为此，两个PDAC细胞系，PANC-1和MiaPaCa-2适应pH6.6或不适应1个月，生长为3D器官型培养物，并在存在和不存在酸中毒和缺氧诱导剂的情况下暴露于GEM或C18，去铁胺.
结果：我们发现，在所有培养条件下，尤其是在酸性和低氧环境中，C18均比GEM具有更高的细胞毒性和抗invadopodia活性。
结论：我们建议C18作为一种更有效的方法来开发克服PDAC化学耐药的新治疗策略。
