7 I, a structurally modified sinomenine, exerts dual anti-GBM effects by inhibiting glioblastoma proliferation and inducing necroptosis which further mediates lysosomal cell death.

Abstract

Background and purpose: Glioblastoma multiforme (GBM) is an aggressive brain tumour which drug treatment has no overall significant effect on survival rate. Sinomenine is a natural product extracted from the traditional Chinese medicine Qingteng and was found to have a certain anti-tumour effect. Although, its short biological half-life, unstable physicochemical properties, large dosage and causes histamine release have hindered its use but it may form the basis for novel drug therapy of GBM.

Experimental approach: We designed, synthesised and screened sinomenine derivative-7 I with high anti-GBM activity and investigated its mechanism of action. Its actions on GBM cells were detected by cell viability assay, RNA-Seq, Western blot, transmission electron microscopy, immunofluorescence along with other methods described.

Key results: 7 I exerted anti-GBM effects through a dual mechanism. 7 I arrested the cell cycle of GBM cells at the G2/M phase by the activation of the P53/P21/CDK1/cyclin B pathway, inhibiting GBM cells proliferation. Secondly, 7 I induced necroptosis of GBM cells through the classical RIPK1/RIPK3/MLKL-dependent pathway causing lysosomal damage and membrane permeabilization leading to lysosomal-mediated cell death. Finally, in vivo xenograft experiments, 7 I significantly inhibited the growth of glioblastoma, effectively reducing inflammation in mice and showing good safety profile.

Conclusions and implications: 7 I, a structurally modified sinomenine, has excellent in vitro and in vivo anti-GBM activity and exerts dual anti-GBM effects by inhibiting glioblastoma proliferation and inducing necroptosis, which further mediates lysosomal cell death. In summary, 7 I is a promising candidate agent for GBM treatment.