Enhancement of gemcitabine toxicity and specificity through PI3K/Akt/Nrf2 pathway inhibition in pancreatic cancer

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with rapid metastasis and chemoresistance driven by PI3K/Akt/Nrf2 signalling and drug efflux transporters. The lack of symptoms and early diagnosis are clinically challenging, and the development of new medications is limited. Therefore, a new strategy to enhance gemcitabine efficacy without increasing systemic toxicity has been demonstrated. Methods: The fragment-based drug sensitiser BD B10 was selected from a Maybridge fragment library using the Tanimoto coefficient to identify structural similarity to trigonelline and tryptamine. PDAC cell lines and non-cancerous pancreatic cells were reated with gemcitabine, BD B10, or their combination. Cell viability, apoptosis, migration, and signalling pathways were analysed using microscopy, flow cytometry, RT-qPCR, Western blot, and RNA Seq with pathway analysis. Results: Applying BD B10 in PDAC cell lines reduced the dose requirement of gemcitabine by 10%, with no adverse effects on growth of non-cancerous pancreatic cell lines, enhancing drug efficacy by 12%, with a otential marked gain in therapeutic index. Additionally, combination treatment enhanced apoptosis, reduced migration, and impeding PI3K/Akt/Nrf2, STAT3, and Wnt/β-catenin signalling regulation. Discussion: BD B10 was identified as a non-toxic drug sensitiser that enhanced gemcitabine efficacy in PDAC cells and improved the therapeutic index by inhibiting key survival and resistance pathways. Specific roles for BD B10 in PDAC were identified and further testing may prove drug sensitisers have a more general application to enhance drug therapies.