ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Predictive Toxicology
This article is part of the Research TopicEnhancing toxicity prediction through adverse outcome pathways: A comprehensive approachView all 3 articles
Enhancement of gemcitabine toxicity and specificity through PI3K/Akt/Nrf2 pathway inhibition in pancreatic cancer
Provisionally accepted
- 1The University of Manchester, Manchester, United Kingdom
- 2University of Cape Town, Rondebosch, South Africa
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
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.
Keywords: binary drug, chemoresistance, drug sensitiser, enhanced drug efficacy, PDAC, PI3K/Akt/Nrf2 pathway
Received: 14 Oct 2025; Accepted: 05 Jan 2026.
Copyright: © 2026 Chen, O'Hagan and Day. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Philip Day
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.