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

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with rapid metastasis and chemoresistance. The lack of symptoms and early diagnosis are clinically challenging, and the development of new medications is limited. We established a means to enhanced killing of pancreatic cancer cells by targeting drug resistance related efflux transporters and key oncogenic pathways. We achieved this through the co-administration of a non-toxic drug sensitiser. We termed this group of drug sensitisers binary drugs (BDs), and we show how BD B10 structurally resembles trigonelline, a PI3K/Akt inhibitor, and tryptamine, a natural metabolite substrate for PI3K/Akt regulation in cancers. BD B10 increased gemcitabine efficacy in PDAC cells causing additional toxicity by impeding PI3K/Akt/Nrf2 regulation. 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 potential marked gain in therapeutic index. 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.<br/><br/>