Difluoromethylornithine Combined With A Polyamine Transport Inhibitor Is Effective Against Gemcitabine Resistant Pancreatic Cancer

Keywords

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

Abstract

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.

Publication Date

2-5-2018

Publication Title

Molecular Pharmaceutics

Volume

15

Issue

2

Number of Pages

369-376

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1021/acs.molpharmaceut.7b00718

Socpus ID

85041662286 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85041662286

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