Structures/cytotoxicity/selectivity relationship of natural steroidal saponins against GSCs and primary mechanism of tribulosaponin A

Zhi Dai; Hui Liu; Bei Wang; Dong Yang; Yan-Yan Zhu; Huan Yan; Pei-Feng Zhu; Ya-Ping Liu; Hui-Cheng Chen; Yun-Li Zhao; Li-Xing Zhao; Xu-Dong Zhao; Hai-Yang Liu; Xiao-Dong Luo

doi:10.1016/j.ejmech.2020.113068

Structures/cytotoxicity/selectivity relationship of natural steroidal saponins against GSCs and primary mechanism of tribulosaponin A

Eur J Med Chem. 2021 Jan 15:210:113068. doi: 10.1016/j.ejmech.2020.113068. Epub 2020 Dec 2.

Authors

Zhi Dai¹, Hui Liu², Bei Wang², Dong Yang³, Yan-Yan Zhu¹, Huan Yan², Pei-Feng Zhu², Ya-Ping Liu², Hui-Cheng Chen¹, Yun-Li Zhao¹, Li-Xing Zhao¹, Xu-Dong Zhao⁴, Hai-Yang Liu⁵, Xiao-Dong Luo⁶

Affiliations

¹ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China.
² State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China.
³ Laboratory of Animal Tumor Models, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.
⁴ Laboratory of Animal Tumor Models, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China. Electronic address: zhaoxudong@wchscu.cn.
⁵ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China. Electronic address: haiyangliu@mail.kib.ac.cn.
⁶ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China. Electronic address: xdluo@mail.kib.ac.cn.

PMID: 33310292
DOI: 10.1016/j.ejmech.2020.113068

Abstract

Glioblastoma multiform (GBM) is the highly aggressive brain tumor with poor prognosis. Glioma stem cells (GSCs), small population of cancer cells that exist in GBM tissues, resistant to chemotherapy and radiotherapy and usually driving GBM recurrence, have been developed as effective therapeutic target. Steroidal saponins are one of important resources for anti-tumor agent and may be benefited to selectively clear GSCs. In this report, total of 97 natural steroidal saponins were investigated the relationship among structures/cytotoxicity/selectivity against GSCs, glioma cell lines and human untransformed cells, and revealed that tribulosaponin A was the most potent compound. Further investigation suggested that tribulosaponin A up-regulated the expression of NCF1 and NOX1 to accumulate ROS for triggering apoptosis in GSCs, but not in untransformed cells, and it was further supported by the assay that N-acetyl-l-cysteine (NAC) clearing ROS delayed GSCs apoptosis. Besides, tribulosaponin A damaged GSCs recapturing tumor spheres formation.

Keywords: Glioma stem cells; ROS; Steroidal saponins; Structure-activity relationship; Tribulosaponin A.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Biological Products / chemical synthesis
Biological Products / chemistry
Biological Products / pharmacology*
Brain Neoplasms / drug therapy*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Glioblastoma / drug therapy*
Glioblastoma / metabolism
Glioblastoma / pathology
Goosecoid Protein / antagonists & inhibitors*
Goosecoid Protein / metabolism
Humans
Molecular Structure
Saponins / chemical synthesis
Saponins / chemistry
Saponins / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Biological Products
GSC protein, human
Goosecoid Protein
Saponins