Pancreatic cancer cells exhibit a remarkable ability to tolerate nutrient deprivation, a phenomenon termed “austerity,” which enables their survival within the hypovascular tumor microenvironment. Conventional anticancer therapies frequently fail to effectively target these resilient neoplastic cells, posing a significant challenge to the therapeutic management of pancreatic cancer. Consequently, targeting austerity, the ability of cancer cells to tolerate nutrient starvation, represents a promising anti-austerity strategy for developing novel pancreatic cancer therapeutics. In this study, we investigated calliviminone A (CVM-A), a phloroglucinol–meroterpenoid isolated from Callistemon citrinus leaves, for its anti-austerity activity against PANC-1 human pancreatic cancer cells. Calliviminone A exhibited potent preferential cytotoxicity in nutrient-deprived medium (NDM) with a PC₅₀ of 0.57 µM, while showing minimal toxicity in nutrient-rich Dulbecco’s Modified Eagle’s medium (IC₅₀ = 45.2 µM), indicating a favorable therapeutic index. Real-time live-cell imaging revealed that CVM-A induced significant morphological changes, including cell shrinkage and membrane blebbing, leading to cell death within 24 h of NDM. Furthermore, under normal nutrient conditions in Dulbecco’s Modified Eagle’s Medium (DMEM), CVM-A significantly inhibited PANC-1 cell migration (up to 47% reduction at 20 µM) and colony formation (over 80% suppression at 25 µM), suggesting its antimetastatic potential. Western blot studies demonstrated that CVM-A downregulated key survival components of the PI3K/Akt/mTOR signaling pathway, completely inhibiting Akt and p-Akt at 2.5 µM in NDM, and suppressing insulin-induced Akt activation. These findings highlight CVM-A as a promising lead compound for developing novel anticancer therapies that target the adaptive survival mechanisms and metastatic potential of pancreatic cancer in nutrient-deprived microenvironments.

The hypovascular nature of pancreatic tumors creates a nutrient-scarce, hypoxic microenvironment, yet pancreatic cancer cells adapt by altering their metabolism to thrive under austere conditions—a phenomenon known as “austerity.” Targeting this adaptation offers a promising strategy for next-generation therapeutics that selectively impair pancreatic cancer cell viability in nutrient-deprived states without toxicity under nutrient-rich conditions. Here, we evaluated the anti-pancreatic cancer properties of grandifloridin D, a synthetic derivative of (+)-grandifloracin. In vitro antiausterity assays demonstrated that grandifloridin D potently and preferentially reduced the viability of MIA PaCa-2 pancreatic cancer cells under nutrient deprivation at a PC50 concentration of 0.14 μM. Live-cell imaging and ethidium bromide/acridine orange (EB/AO) dual staining confirmed that grandifloridin D induces cell death by disrupting membrane integrity. Under nutrient-rich conditions, grandifloridin D exhibited antimetastatic activity, significantly inhibiting MIA PaCa-2 cell migration in real-time assays and suppressing colony formation and spheroid formation. Western blot analysis revealed that grandifloridin D is a potent inhibitor of the protein kinase B (Akt) and mammalian target of rapamycin (mTOR) signaling pathway while also suppressing the autophagy-related proteins microtubule-associated protein 1 light chain 3 (LC3). These results suggest that grandifloridin D is a promising antiausterity agent for pancreatic cancer drug development.