期刊
BMC CANCER
卷 22, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12885-022-09857-x
关键词
Chondrosarcoma; Shikonin; Acetylshikonin; Cyclopropylshikonin; Apoptosis; Death receptors; MAPK signaling
类别
资金
- Medical University of Graz
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation
Shikonin and its derivatives show dose-dependent inhibition of chondrosarcoma cell viability, induce cell cycle arrest, and modulate protein and gene expression. They downregulate survivin and XIAP expression and upregulate Noxa, γH2AX, cleaved caspase, and PARP expression, as well as modulate the expression of various death receptors. Furthermore, shikonin derivatives affect the phosphorylation pattern of the MAPK signaling pathway and its downstream gene regulation.
Background Although chondrosarcoma is the second most common primary malignant bone tumor, treatment options are limited due to its extensive resistance to a chemo- and radiation therapy. Since shikonin has shown potent anticancer activity in various types of cancer cells, it represents a promising compound for the development of a new therapeutic approach. Methods The dose-relationships of shikonin and its derivatives acetylshikonin and cyclopropylshikonin on two human chondrosarcoma cell lines were measured using the CellTiter-Glo (R). The changes in the cell cycle were presented by flow cytometry. Protein phosphorylation and expression apoptotic markers, MAPKs and their downstream targets were analyzed using western blotting and gene expression were evaluated using RT-qPCR. Results Chondrosarcoma cells showed a dose-dependent inhibition of cell viability after treatment with shikonin and its derivatives, with the strongest effect for shikonin and IC50 values of 1.3 +/- 0.2 mu M. Flow cytometric measurements revealed a G(2)/M arrest of the cells after treatment. Protein and gene expression analysis demonstrated a dose-dependent downregulation of survivin and XIAP, and an upregulation of Noxa, gamma H2AX, cleaved caspase-8, -9, -3, and -PARP. Furthermore, the expression of various death receptors was modulated. As MAPK signaling pathways play a key role in tumor biology, their phosphorylation pattern and their corresponding downstream gene regulation were analyzed. Treatment with shikonin derivatives caused an inhibition of pSTAT3 and an increase of pAKT and the MAPKs pERK, pJNK, and pp38 in a dose-dependent manner. Conclusions These data demonstrated the significant anti-tumorigenic effect of shikonin derivatives in chondrosarcoma and encourage further research.
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