PUBLICATION
Tanshinol suppresses osteosarcoma by specifically inducing apoptosis of U2-OS cells through p53-mediated mechanism
- Authors
- Yu, S., Guo, L., Yan, B., Yuan, Q., Shan, L., Zhou, L., Efferth, T.
- ID
- ZDB-PUB-220326-11
- Date
- 2022
- Source
- Journal of ethnopharmacology 292: 115214 (Journal)
- Registered Authors
- Keywords
- MG-63, Osteosarcoma, Radix Salviae miltiorrhizae, Tanshinol, U2-OS, Zebrafish
- MeSH Terms
-
- Adolescent
- Animals
- Apoptosis
- Bone Neoplasms*/drug therapy
- Caffeic Acids
- Cell Line, Tumor
- Cell Proliferation
- Humans
- Osteosarcoma*/drug therapy
- Osteosarcoma*/metabolism
- Osteosarcoma*/pathology
- Salvia miltiorrhiza*
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Zebrafish
- bcl-2-Associated X Protein/metabolism
- PubMed
- 35331874 Full text @ J. Ethnopharmacol.
Citation
Yu, S., Guo, L., Yan, B., Yuan, Q., Shan, L., Zhou, L., Efferth, T. (2022) Tanshinol suppresses osteosarcoma by specifically inducing apoptosis of U2-OS cells through p53-mediated mechanism. Journal of ethnopharmacology. 292:115214.
Abstract
Ethnopharmacological relevance Radix Salviae miltiorrhizae (also called Danshen in traditional Chinese medicine) is a famous herbal medicine, which has been frequently used to treat blood stasis syndrome including osteosarcoma (OS) in traditional Chinese medicine. Main components of Danshen have been assumed to exhibit anti-OS capacity. Nevertheless, tanshinol (TS, main component of Danshen)'s efficacy and mechanism in OS hasn't been clearly described ever since. This drew our attention, since OS is the most frequent primary bone carcinomas in children and adolescents, with a high incidence and fatality rate. Unfortunately, chemotherapy for OS has faced many clinical challenges due to the increasing chemoresistance and recurrence. This study was then designed to deeply explore TS's role in OS therapy.
Aim of the study To explore the anti-OS efficacy and mechanism of TS, we conducted in vivo and in vitro experiments by using a zebrafish xenograft model and U2-OS cells.
Materials and methods CCK-8 assay, DAPI and γ-H2A.X immunofluorescence staining, and flow cytometry (apoptosis verification) were employed to determine the anti-proliferative and pro-apoptotic effects of TS. qPCR and western blot were used to examine TS's molecular actions and mechanism on apoptosis of U2-OS cells.
Results The in vivo data showed that TS significantly inhibited U2-OS tumor growth in larval zebrafish from 2 to 20 ng/mL. In vitro data indicated that TS exerted significant anti-proliferative and pro-apoptotic effects on U2-OS cells in a dose-dependent manner. Moreover, TS has no inhibitory effect on bMSCs, suggesting its safety on normal bone-forming cells. Molecular data illustrated that TS obviously activated the p53 signaling-related proteins (p-p53, Bax, CASP3, CASP9) and its upstream JNK (p-JNK, p-c-JUN) and ATM (p-ATM) signaling molecules through phosphorylation and cleavage, followed by up-regulation of the pro-apoptotic genes, NOXA, PUMA, TP53, BAX, and BIM, and down-regulation of Bcl-2 protein.
Conclusion In sum, TS specifically induced apoptosis of U2-OS cells by activating p53 signaling pathways, indicating TS as a promising candidate for OS treatment.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping