The native polyamines putrescine, spermidine, and spermine are essential for cell development and proliferation. Polyamine levels are often increased in cancer tissues and polyamine depletion is a validated anticancer strategy. Cancer cell growth can be inhibited by the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), which inhibits ornithine decarboxylase (ODC), the rate-limiting enzyme in the polyamine biosynthesis pathway. Unfortunately, cells treated with DFMO often replenish their polyamine pools by importing polyamines from their environment. Several polyamine-based molecules have been developed to work as polyamine transport inhibitors (PTIs) and have been successfully used in combination with DFMO in several cancer models. Here, we present the first comprehensive search for potential non-polyamine based PTIs that work in human pancreatic cancer cells in vitro. After identifying and testing five different categories of compounds, we have identified the c-RAF inhibitor, GW5074, as a novel non-polyamine based PTI. GW5074 inhibited the uptake of all three native polyamines and a fluorescent-polyamine probe into human pancreatic cancer cells. GW5074 significantly reduced pancreatic cancer cell growth in vitro when treated in combination with DFMO and a rescuing dose of spermidine. Moreover, GW5074 alone reduced tumor growth when tested in a murine pancreatic cancer mouse model in vivo. In summary, GW5074 is a novel non-polyamine-based PTI that potentiates the anticancer activity of DFMO in pancreatic cancers.

天然多胺腐胺、亚精胺和精胺对细胞发育和增殖至关重要。癌症组织中的多胺水平通常会增加，而多胺消耗是一种经过验证的抗癌策略。多胺生物合成抑制剂二氟甲基鸟氨酸 (DFMO) 可抑制癌细胞生长，该抑制剂可抑制多胺生物合成途径中的限速酶鸟氨酸脱羧酶 (ODC)。不幸的是，用 DFMO 处理的细胞通常通过从其环境中导入多胺来补充其多胺池。几种基于多胺的分子已被开发用作多胺转运抑制剂 (PTI)，并已成功与 DFMO 结合用于多种癌症模型。这里，体外。在鉴定和测试五种不同类别的化合物后，我们将 c-RAF 抑制剂 GW5074 鉴定为一种新型的非多胺基 PTI。GW5074 抑制所有三种天然多胺和荧光多胺探针进入人类胰腺癌细胞的摄取。当与 DFMO 和拯救剂量的亚精胺联合治疗时， GW5074在体外显着降低胰腺癌细胞的生长。此外，当在小鼠胰腺癌小鼠模型中进行体内测试时，GW5074 单独降低了肿瘤的生长。总之，GW5074 是一种新型的非多胺基 PTI，可增强 DFMO 在胰腺癌中的抗癌活性。