Pancreatic Cancer Chemoresistance to Gemcitabine

Abstract

Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated. Many of these approaches are reported to be more efficient than the parent gemcitabine molecule when tested in cellular systems and in vivo in murine tumor model systems; however, although promising, their translation to clinical use is still in a very early phase. This review discusses gemcitabine metabolism, activation and chemoresistance entities in the gemcitabine cytotoxicity pathway and provides an overview of approaches to override chemoresistance in pancreatic cancer.

Keywords: chemoresistance; gemcitabine; pancreatic ductal adenocarcinoma; tumor stroma.

Figure 1

Gemcitabine molecule and its modification sites (4-(N) and 5′-OH).

Figure 2

Gemcitabine: transport, intracellular activation/deactivation and mechanism of action. CDA: cytidine deaminase, dCK: deoxycytidine kinase, DCTD: deoxycytidylate deaminase, dFdC: 2′,2′-difluorodeoxycytidine, dFdU: 2′,2′-difluorodeoxyuridine, hENTs and hCNTs: human nucleoside transporters, NDPK: nucleoside diphosphate kinase, NMPK: nucleoside monophosphate kinase, RR(M1/M2), ribonucleotide reductase, 5′-NT: 5′-nucleotidase.

Figure 3

Approaches being explored to target pancreatic tumor using gemcitabine-based nanomedicines. Different nanocarriers, such as liposome, micelle, nanocapsule, nanosphere, polymeric nanoparticle, solid-lipid nanoparticle and conjugated-nanoparticle, have been developed for effective delivery of gemcitabine to pancreatic tumor cells. Strategies for the efficacy of gemcitabine using nanomedicines include, but are not limited to increased drug availability via protection from first-pass metabolism, passive accumulation at the tumor site due to the enhanced permeability and retention (EPR) effect, as well as targeted delivery of gemcitabine to tumor cells