The marine natural product Scalarin inhibits the receptor for advanced glycation end products (RAGE) and autophagy in the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines

Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Although combination therapies are showing improvements in treatment, the survival rate for pancreatic cancer five years post diagnosis is only 8%, stressing the need for new treatments. The receptor for advanced glycation end products (RAGE) has recently emerged as a chemotherapeutic target in KRAS driven pancreatic cancers both for treatment and in chemoprevention. RAGE appears to be an important regulator of inflammatory, stress and survival pathways that lead to carcinogenesis, resistance to chemotherapy, enhanced proliferation and the high metastatic potential of pancreatic cancer. RAGE expression has been demonstrated in pancreatic cancer tumors but not in adjacent epithelial tissues. Its presence is associated with increased proliferation and metastasis. In an effort to identify novel inhibitors of RAGE among our collection of marine-derived secondary metabolites, a cell-based screening assay utilizing flow cytometry was developed. This effort led to the identification of scalarin as the active compound in a marine sponge identified as Euryspongia cf. rosea. Scalarin is a sesterterpene natural product isolated previously from a different marine sponge. Scalarin reduces the levels of RAGE and inhibits autophagy in the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines. Its IC₅₀ for cytotoxicity ranges between 20 and 30 μM in the AsPC-1, PANC-1, MIA PaCa-2 and BxPC-3 pancreatic cancer cell lines. Inhibition of autophagy limits tumor growth and tumorigenesis in pancreatic cancer, making scalarin an interesting compound that may merit further study.