Pancreatic ductal adenocarcinoma (PDAC) is highly chemo-resistant and has an extremely poor patient prognosis, with a survival rate at five years of <8%. There remains an urgent need for innovative treatments. Targeting polyamine biosynthesis through inhibition of ornithine decarboxylase with difluoromethylornithine (DFMO) has had mixed clinical success due to tumor escape via an undefined transport system, which imports exogenous polyamines and sustains intracellular polyamine pools. Here, we tested DFMO in combination with a polyamine transport inhibitor (PTI), Trimer44NMe, against Gemcitabine-resistant PDAC cells. DFMO alone and with Trimer44NMe significantly reduced PDAC cell viability by inducing apoptosis or diminishing proliferation. DFMO alone and with Trimer44NMe also inhibited in vivo orthotopic PDAC growth and resulted in decreased c-Myc expression, a readout of polyamine pathway dysfunction. Moreover, dual inhibition significantly prolonged survival of tumor-bearing mice. Collectively, these studies demonstrate that targeting polyamine biosynthesis and import pathways in PDAC can lead to increased survival in pancreatic cancer.

中文翻译：

---

二氟甲基鸟氨酸结合多胺转运抑制剂可有效抵抗吉西他滨耐药的胰腺癌。

胰腺导管腺癌（PDAC）具有高度的化学耐药性，患者预后极差，五年生存率<8％。迫切需要创新的治疗方法。通过二氟甲基鸟氨酸（DFMO）抑制鸟氨酸脱羧酶来靶向多胺生物合成，由于肿瘤通过不确定的转运系统逸出而转移了临床成功，该转运系统进口外源多胺并维持细胞内多胺池。在这里，我们测试了DFMO与多胺转运抑制剂（PTI）Trimer44NMe联合使用对吉西他滨耐药的PDAC细胞的作用。单独使用DFMO并与Trimer44NMe一起使用，会诱导凋亡或减少增殖，从而显着降低PDAC细胞的生存能力。单独使用DFMO以及与Trimer44NMe一起使用时，DFMO也会抑制体内原位PDAC的生长，并导致c-Myc表达下降，这是多胺途径功能障碍的一种表现。此外，双重抑制显着延长了荷瘤小鼠的生存期。总而言之，这些研究表明，在PDAC中靶向多胺生物合成和导入途径可以导致胰腺癌的生存期延长。