Cucurbitane triterpenoid entities derived from Hemsleya penxianensis triggered glioma cell apoptosis via ER stress and MAPK signalling cross-talk

In the present study, six new cucurbitane type compounds, including three triterpenoids hemsleyacins P-R (6–7, 13) and three cucurbitane-type triterpenoid glycosides hemsleyaosides L-N (15–17), along with seventeen known cucurbitacin analogues were separated from the root tuber of Hemsleya penxianensis and elucidated based on NMR and HRESIMS. Then, 23 analogues of three types, namely, polyhydroxy-type (I) (1–7), monohydroxy-type (II) (8–13), and glycosides-type (III) (14–23), were assessed for their antitumor activity and structure–activity relationship analysis (SAR). We determined temozolomide (TMZ)-resistant GBM cell was the most sensitive to the tested compounds, and found hemsleyaoside N (HDN) displayed the best antineoplastic potency. Furthermore, we confirmed the anti-glioma activity of HDN in patient-derived recurrent GBM strains, GBM organoid (GBO) and orthotopic nude mouse models. Investigations exploring the mechanism made clear that HDN induced synchronous activation of UPR and MAPK signaling, which triggered deadly ER stress and apoptosis. Taken together, the potent antitumor activity of HDN warrants further comprehensive evaluation as a novel anti-glioma agent.