Abstract
Aim: Because mutations of splicing factor 3B subunit-1 (SF3B1) have been identified in 4% of pancreatic ductal adenocarcinoma (PDAC) patients, we investigated the activity of new potential inhibitors of SF3B1 in combination with gemcitabine, one of the standard drugs, in PDAC cell lines. Methods: One imidazo[2,1-b][1,3,4]thiadiazole derivative (IS1) and three indole derivatives (IS2, IS3 and IS4), selected by virtual screening from an in-house library, were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2, Hs766t and Panc05.04, the latter harbouring the SF3B1 mutations. The effects on the splicing pattern of proto-oncogene recepteur d’origine nantais (RON) and the gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT1) were assessed by PCR, while the ability to reduce tumour volume was tested in spheroids of primary PDAC cells. Results: The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell death. All compounds showed an interesting anti-migratory ability, associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h exposure. Moreover, IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures, and these results might be explained by the statistically significant increase in hENT1 expression (P < 0.05 vs. untreated control cells), potentially reversing PDAC chemoresistance. Conclusion: These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world
IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures, and these results might be explained by the statistically significant increase in human equilibrative nucleoside transporter-1 (hENT1) expression (P < 0.05 vs. untreated control cells), potentially reversing PDAC chemoresistance
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 focused on the effect of alternative splicing (AS) on hENT1 expression in order to bypass one of the most important mechanism involved in the resistance to gemcitabine
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world. PDAC is projected to become the second leading cause of cancer-related death by 2030[3]. The only current curative treatment at the moment is surgical resection, which is possible in only 20% of patients. This treatment has a high complication rate and recurrence is often seen[6]. The standard of care treatment is chemotherapy, using polychemotherapy regimens or gemcitabine monotherapy[7]. Gemcitabine, approved by the Food and Drug Administration in 1996, was the standard of care in the treatment of locally advanced and metastatic PDAC for over two decades. A better efficacy was found for various chemotherapy combinations such as FOLFIRINOX [5fluorouracil, folinic acid (leucovorin), irinotecan, oxaliplatin] and gemcitabine plus nab-paclitaxel (GEMNAB, Abraxane®)[8]
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