Droserone and dioncoquinone B, and related naphthoquinones as potent antiausterity agents against human PANC-1 pancreatic cancer cells

Pancreatic cancer is a highly aggressive disease with a poor prognosis. Its tumor microenvironment is characterized by severe nutrient deprivation and hypoxia, leading to the activation of adaptive pathways that allow cancer cells to survive and thrive under these harsh conditions. This makes conventional therapies less effective, highlighting the urgent need for novel treatment strategies. Naphthoquinones have recently emerged as promising anti-austerity agents, demonstrating preferential cytotoxicity against pancreatic cancer cells in nutrient-deprived medium (NDM). To further explore their potential, we investigated the structure–activity relationships and mechanism of action of a library of 28 natural and synthetic naphthoquinones. Our results reveal a significant influence of functional groups at positions C-2, C-3, C-5, and C-6 on anticancer activity. Strong electron-donating substituents at C-3 decreased the activity, while electron-withdrawing groups at C-3 and H-bond acceptors at C-6 (without H-bond donor activity) increased the potency. The naphthoate esters 4 and 5 exhibited the strongest activity against PANC-1 cells, with PC₅₀ values of 0.87 and 0.42 μM, respectively. These compounds significantly altered cancer cell morphology, induced apoptosis, and inhibited colony formation. Further investigation revealed that compound 5 downregulated the expression of Akt and p-Akt(S473) proteins, suggesting that its anti-austerity activity might involve suppression of the Akt signaling pathway. These findings demonstrate the immense potential of naphthoquinones as novel anticancer agents targeting the austerity-adapted pancreatic cancer cells. Further development of these promising compounds holds significant potential for treating this devastating disease.