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.
Highlights
Glioblastoma is the most common malignant brain tumor with average only 14 months survival time and constitutes about 50% of all brain parenchymal tumors
To determine whether 3α-acetonyltabersonine (Figure 1A) could be cytotoxic to glioblastoma, two glioblastoma stem cells (GSCs) isolated from clinic samples and two widely used cell lines, U87 and T98G, were used to conduct [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]
Acetonyltabersonine‐treated group, a marked reduction in red fluorescence and an increase in green fluorescence were observed in the cells, indicating the loss of membrane potential (MMP) and the induction of apoptosis
Summary
Glioblastoma is the most common malignant brain tumor with average only 14 months survival time and constitutes about 50% of all brain parenchymal tumors. In our continual search for natural antitumor products from medicinal plants, indole alkaloids were found to be the most potent candidates in a cytotoxicity bioassay against five human cancer cell lines [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29] Among these cytotoxic indoles, 3α-acetonyltabersonine, an aspidosperma-type monoterpenoid indole alkaloid, structurally similar to vindoline, showed the best bioactivity, with IC50 values of 0.2–0.6 μM against human myeloid leukemia. 3α-acetonyltabersonine could induce cell apoptosis in vivo and prolong the survival span of glioblastoma mouse model
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have