Eudesmane-guaiane sesquiterpenoid dimers from Aucklandia costus trigger paraptosis-like cell death via ROS accumulation and MAPK hyperactivation

Three new sesquiterpenoid heterodimers, auckcostusolides A–C (1–3), were isolated from the leaves of Aucklandia costus. The structures of compounds 1–3 were elucidated through extensive spectroscopic analysis, and their absolute configurations were established through a combination of X-ray single-crystal diffractions and electronic circular dichroism (ECD) calculations. Interestingly, compounds 1 and 2, while processing the same planar structures originating from two identical sesquiterpenoids, exhibited opposite configurations at C-11 and C-8′. This distinction in configuration can be attributed to the different Diels−Alder cycloaddition between two sesquiterpenoid monomers. Furthermore, the cytotoxic effects of compounds 1–3 were assessed against colorectal cancer HCT116 cells, fibrosarcoma HT1080 cells, and hepatocellular carcinoma HepG2 cells. Compounds 1–3 could trigger cell death with ER swelling and cytoplasmic vacuolization, which is a typical morphological change of paraptosis. Mechanistically, compounds 1 and 3 triggered paraptosis-like cell death through the accumulation of reactive oxygen species (ROS), the activation of endoplasmic reticulum (ER) stress, and the MAPK signaling pathway.