Isoquinolinequinone N-Oxides as Promising Antitumor Compounds in Pancreatic Cancer Cell Lines

Background: Pancreatic ductal adenocarcinoma (PDAC) represents the 12th most commonly diagnosed malignancy worldwide and the sixth leading cause of cancer-related mortality, with more than 500,000 new cases and nearly 470,000 deaths recorded in 2022 1. Its poor prognosis is largely driven by intrinsic and acquired drug resistance, leading to mortality rates above 90%. Current treatment mainly relies on gemcitabine, either alone or in combination with paclitaxel 2,3, highlighting the urgent need for novel anticancer agents, particularly those able to overcome chemoresistance. Recently, isoquinolinequinone (IQQ) N-oxides have shown promising antitumor activity in pairs of sensitive and multidrug-resistant (MDR) lung and colorectal cancer cell models 4,5. Objective: This study aimed to evaluate the antitumor effects of IQQ N-oxides in several PDAC models, including a sensitive and resistant PDAC cell line. Methods: MiaPaCa-2, Capan-1, BxPC-3, Panc-1, and the resistant Panc-1-CDR PDAC cells were treated with different concentrations of IQQ N-oxides (RK1-RK9) or gemcitabine for 48 h. Cell viability was assessed by SRB assay, while long-term clonogenic potential was determined by colony formation assay (2 or 6 days). Anti-migratory effects were evaluated using a wound healing assay over 48 h. Results: RK2 and RK3 emerged as the most potent derivatives, with GI50 values ranging from 0.80 to 2.35 µM across multiple cell lines. Both compounds remained effective in the gemcitabine-resistant Panc-1-CDR model, with GI50 values of 1.41 and 1.14 µM, respectively. Moreover, the clonogenic assay showed a marked concentration and time-dependent reduction in colony formation, with near-complete inhibition by day 6 when Panc-1 cells were treated with RK2 and RK3. Additionally, treatment with RK2 and RK3 significantly impaired cell migration at 1µM concentration, limiting wound closure to 60% and 51%, respectively, after 48h (compared to 80% in control cells). Conclusions: The IQQ N-oxide derivatives, RK2 and RK3, effectively reduced PDAC cell growth, including in a gemcitabine-resistant PDAC cell line, and suppressed key malignant traits such as self-renewal and migration, supporting their potential as promising therapeutic leads for PDAC.