Difluoromethylornithine Combined with a Polyamine Transport Inhibitor Is Effective against Gemcitabine Resistant Pancreatic Cancer

作者：Gitto Sarah B; Pandey Veethika; Oyer Jeremiah L; Copik Alicja J; Hogan Frederick C; Phanstiel Otto; Altomare Deborah A^*

来源：Molecular Pharmaceutics, 2018, 15(2): 369-376.

DOI：10.1021/acs.molpharmaceut.7b00718

• polyamine biosynthesis
• polyamine transport
• pancreatic cancer
• therapy
• c-Myc

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 pcilyamine 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.

• 出版日期2018-2