Novel nor-monoterpenoid indole alkaloids inhibiting glioma stem cells from fruits of Alstonia scholaris.

Abstract

BACKGROUND:

Glioblastoma multiforme (GBM) is a highly aggressive and frequently recurrent malignant brain tumor, and to date, the clinically effective drugs against GBM remain scarce. Natural products play an important role in drug discovery, and might be the resource of antitumor agents for GSCs. Alstonia scholaris (L.) R. Br. is rich in monoterpenoid indole alkaloids (MIAs) and used extensively for treatment of tumor in the traditional medicine system of Asia.

PURPOSE:

To search for new MIAs with antitumor activity against glioma stem cells from clinical patients and explore their mechanism.

METHODS:

Compounds were obtained from the fruits of A. scholaris by chromatographic separation, including silica gel, Sephadex LH-20 and recrystallization. Their structures were elucidated by the use of UV, IR, NMR and MS spectra. The antitumor activity of the compounds against the glioma stem cells (GSC-3#, GSC-12#, GSC-18#) were investigated by phenotypic screening and MTS assays. Cell proliferation assay by BrdU immunofluorescence staining, and apoptosis assay by cleaved-caspase-3 immunofluorescence staining and real-time PCR assay. The soft-agar clonal formation assay was performed to determine the antitumor efficacy of the compounds in vitro.

RESULTS:

Two new nor-monoterpenoid indole alkaloids were isolated from the fruits of A. scholaris. They exhibited selective antitumor activity against glioma stem cells (GSC-3#, GSC-12#, GSC-18#) with IC50 values of 15-25 µg/ml. Furthermore, they inhibited GSCs proliferation, induced GSCs apoptosis by increasing the expression of TNF-α and cleavage of caspase-3, and significantly damaged colony forming capacity of GSCs.

CONCLUSION:

New nor-monoterpenoid indole alkaloids from the fruits of A. scholaris provide new type promising molecule for the selective killing of human glioma stem cells.

• Authors: Bei Wang, Zhi Dai, Xiong-Wu Yang, Ya-Ping Liu, Afsar Khan, Zi-Feng Yang, Wan-Yi Huang, Xin-Hua Wang, Xu-Dong Zhao, Xiao-Dong Luo
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 48 Pg. 170-178 (Sep 15 2018) ISSN: 1618-095X [Electronic] Germany
• PMID: 30195875 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier GmbH. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Secologanin Tryptamine Alkaloids
• CASP3 protein, human
• Caspase 3

Topics

• Alstonia (chemistry)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy)
• Caspase 3 (metabolism)
• Cell Line
• Fruit (chemistry)
• Glioblastoma (drug therapy)
• Glioma (drug therapy)
• Humans
• Magnetic Resonance Spectroscopy
• Molecular Structure
• Neoplastic Stem Cells (drug effects)
• Secologanin Tryptamine Alkaloids (pharmacology)