Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Lohberger, B; Kaltenegger, H; Eck, N; Glänzer, D; Leithner, A; Kretschmer, N.
The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model.
Int J Mol Sci. 2023; 24(21):
Doi: 10.3390/ijms242115910
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- Führende Autor*innen der Med Uni Graz
- Lohberger Birgit
- Co-Autor*innen der Med Uni Graz
- Eck Nicole
- Glänzer Dietmar
- Kaltenegger Heike
- Kretschmer Nadine
- Leithner Andreas
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- Abstract:
- Myxofibrosarcoma (MFS) is a subtype of soft tissue sarcoma of connective tissue, which is characterized by large intra-tumor heterogeneity. Therapy includes surgical resection. Additional chemotherapy is of limited effect. In this study, we demonstrated the potent anticancer activity of shikonin derivatives in our MFS cellular model of tumor heterogeneity for developing a new therapeutic approach. The impact of shikonin and β,β-dimethylacrylshikonin (DMAS) on viability, apoptotic induction, MAPK phosphorylation, and DNA damage response were analyzed by means of two human MFS cell lines, MUG-Myx2a and MUG-Myx2b, derived from a singular tumor tissue specimen. MFS cells showed a dose-dependent inhibition of cell viability and a significant induction of apoptosis. Treatment with shikonin derivatives caused an inhibition of pSTAT3 and an increase in pAKT, pERK, pJNK, and pp38. DMAS and shikonin inhibited the activation of the two master upstream regulators of the DNA damage response, ATR and ATM. MUG-Myx2b, which contains an additional PTEN mutation, was more sensitive in some targets. These data demonstrate the significant antitumorigenic effect of shikonin derivatives in MFS and highlight the importance of intra-tumor heterogeneity in treatment planning.
- Find related publications in this database (Keywords)
- myxofibrosarcoma
- shikonin
- beta,beta-dimethylacrylshikonin
- apoptosis
- MAPK signaling
- tumor heterogeneity
- DNA damage response