Cytotoxic Indole Alkaloid 3α-Acetonyltabersonine Induces Glioblastoma Apoptosis via Inhibition of DNA Damage Repair

Abstract

Cytotoxic indole alkaloids from Melodinus suaveolens, which belongs to the toxic plant family Apocynaceae, demonstrated impressive antitumor activities in many tumor types, but less application in glioblastoma, which is the lethal brain tumor. In the present study, we reported the anti-glioblastoma activity of an indole alkaloid, 3α-acetonyltabersonine, which was isolated from Melodinus suaveolens. 3α-acetonyltabersonine was cytotoxic to glioblastoma cell lines (U87 and T98G) and stem cells at low concentrations. We verified 3α-acetonyltabersonine could suppress tumor cell proliferation and cause apoptosis in glioblastoma stem cells (GSCs). Moreover, detailed investigation of transcriptome study and Western blotting analysis indicated the mitogen activated protein kinase (MAPK) pathway was activated by phosphorylation upon 3α-acetonyltabersonine treatment. Additionally, we found 3α-acetonyltabersonine inhibited DNA damage repair procedures, the accumulated DNA damage stimulated activation of MAPK pathway and, finally, induced apoptosis. Further evidence was consistently obtained from vivo experiments on glioblastoma mouse model: treatment of 3α-acetonyltabersonine could exert pro-apoptotic function and prolong the life span of tumor-bearing mice. These results in vitro and in vivo suggested that 3α-acetonyltabersonine could be a potential candidate antitumor agent.

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

“…Moreover, 3α-acetonyltabersonine was shown to inhibit the DNA damage repair process and induce apoptosis through the activation of MAPK phosphorylation (p-ERK and p-JNK). And the in vivo experiment showed that 3α-acetonyltabersonine could prolong the survival time of the glioblastoma mouse model [ 140 ]. Additionally, a β-carboline alkaloid, flavopereirine, was also found to trigger cell cycle arrest, suppress the activation of AKT, and increase the ERK and p38 MAPK expression level, ultimately resulting in the induction of apoptosis in MDA-MB-231 cells [ 141 ].…”

Phytochemical Profiling of Balinese Alkaloid-Source Plant Purnajiwa (Kopsia arborea Blume. and Euchresta horsfieldii (Lesch.) Benn.)

“…[56][57][58][59][60] Research shows the cytotoxic effect of tabersonin against various cancer cell cultures. [61][62][63] Terpenoids are other secondary metabolites identified in the purnajiwa sample. The terpenoids identified in the Jimbaran fruits sample is aristolin, while 64 Fatty acids are another class of compounds identified in purnajiwa samples.…”

Research Progress of Indole Alkaloids: Targeting MAP Kinase Signaling Pathways in Cancer Treatment

“…The 3 -acetonyltabersonine was the agent that impeded the repair of DNA damage mechanisms. It is of crucial importance and enhances the anticancer mechanism in indole alkaloids to have 3α-acetonyltabersonine, which prevents DNA damage repair and the buildup of DNA damage that impacts the genome integrity [70].…”