“Open Sesame?”: Biomarker Status of the Human Equilibrative Nucleoside Transporter-1 and Molecular Mechanisms Influencing its Expression and Activity in the Uptake and Cytotoxicity of Gemcitabine in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.

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“…Previously, our imidazo[2,1-b][1, 3,4]thiadiazole compounds in combination with gemcitabine significantly increased the expression of hENT1, suggesting its potential role in increasing the activity of gemcitabine [40] . These promising results prompted us to adopt the same strategy to investigate potential molecular mechanisms underlying the reduced activity of gemcitabine in combination with IS1 and IS4.…”

“…Our previous data show that some compounds from a series of new imidazo[2,1-b][1, 3,4]thiadiazole derivatives potentiated the antiproliferative effects of gemcitabine in peritoneal mesothelioma cells [40] . However, different splicing aberrations have previously been shown to enhance the activity of proliferative and glycolytic signalling associated to gemcitabine resistance [68][69][70] .…”

“…Since gemcitabine is commonly used (in monotherapy or within polychemotherapy regimens) for the treatment of PDAC patients and our previous studies in preclinical models of mesothelioma showed that thiadiazole derivatives potentiated gemcitabine effects [40] , we evaluated the cytotoxic activity of the most promising compounds (IS1 and IS4) in combination with gemcitabine. For these studies, we used the above-described SRB assay exposing cells to IC 50 values of the experimental compounds, added to IC 25 values of gemcitabine, for 72 h, as described previously [40] .…”

“…The promising results obtained in our previous studies concerning the anticancer properties of imidazo[2,1b][1, 3,4]thiadiazole and indole scaffolds [25,[37][38][39][40] prompted us to explore the biological activity of the selected compounds alone and in combination with gemcitabine. Gemcitabine still represents the cornerstone of PDAC treatment and in preclinical models of peritoneal mesothelioma we observed that our imidazo[2,1-b] [1, 3,4]thiadiazole derivatives potentiated its antiproliferative effects [40] .…”

“…The promising results obtained in our previous studies concerning the anticancer properties of imidazo[2,1b][1, 3,4]thiadiazole and indole scaffolds [25,[37][38][39][40] prompted us to explore the biological activity of the selected compounds alone and in combination with gemcitabine. Gemcitabine still represents the cornerstone of PDAC treatment and in preclinical models of peritoneal mesothelioma we observed that our imidazo[2,1-b] [1, 3,4]thiadiazole derivatives potentiated its antiproliferative effects [40] . Since these results were associated with increased expression of hENT1, which plays a key role in the uptake and cytotoxicity of gemcitabine [41] , in the present study, we also focused on the effect of AS on hENT1 expression in order to bypass one of the most important mechanism involved in the resistance to gemcitabine.…”