Abstract
Small cell lung cancer (SCLC) is a high-grade malignancy and prone to drug resistance, with limited progress in patient survival over the past 30 years. Therefore, there is an urgent need to explore new treatment strategies for SCLC patients. Autophagic cell death represents a novel therapeutic strategy for cancer cells with high apoptotic thresholds. Here, we demonstrate that nitrobenzoyl-insulicolide A (1), a new sesquiterpene, isolated from Antarctica sponge-derived fungus Aspergillus insulicola HDN151418, inhibits the proliferation of various SCLC cells including adriamycin- or cisplatin/etoposide-resistant cells, via autophagic death rather than apoptosis, necrosis and cell aging. Molecular mechanism analysis revealed that compound 1 induced autophagic cell death in the NCI-H446 and H69 AR cells dependent on activations of the AKT/mTOR/PARP and ERK1/2 signaling pathways. These findings provide an experimental basis for the further development of 1 as a lead compound against small cell lung cancer in future. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42995-025-00292-y.