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Selected Publication:
Stallinger, A.
ELUCIDATION OF SPECIFIC CYTOTOXIC EFFECTS OF β-β -DIMETHYLACRYLSHIKONIN IN MELANOMA AND CHORDOMA CELLS
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medical University of Graz; 2019. pp. 120
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- Authors Med Uni Graz:
- Advisor:
- Deutsch Alexander
- Rinner Beate
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- Abstract:
- Chordoma and melanoma, one a bone tumour, the other a skin cancer type, are both associated with poor prognosis and low overall survival rates, which is due to missing treatment options. Therefore, the development of novel therapeutics is urgently necessary. β-β-Dimethylacrylshikonin (DMAS), a shikonin derivative, has proven to be a promising new candidate for treatment of several cancer types in preliminary experiments, including melanoma. However, the mechanism of DMAS induced effects on melanoma and chordoma cells are still unknown. In this work, the effects of DMAS on melanoma and chordoma cell lines as well as the affected pathways are elucidated. The influence of DMAS on cell viability was examined with MTS and EZ4U assays and DMAS induced apoptosis was analysed with Annexin V / SYTOX Green staining as well as the active caspase-3 assay. RT-qPCR and Western blots were performed to investigate expression levels of apoptosis and/or survival genes under DMAS treatment. For melanoma cell lines, mRNA sequencing was performed to find potential new candidate genes. Additionally, NOXA knockdown was carried out to show NOXA dependent DMAS treatment effects. Finally, in-vivo studies with melanoma cell lines were conducted to elucidate whether DMAS induced effects in-vitro can also be observed in-vivo. DMAS was found to reduce cell viability in both cancer types in a dose-dependent manner, in melanoma additionally in a time dependent one. Furthermore, DMAS induced apoptosis in melanoma and chordoma cells in-vitro, but apoptosis, necrosis and fibrosis in melanoma derived tumours in-vivo. Concerning affected pathways, only NOXA was significantly upregulated in both cancer types on genetical as well as protein level. NOXA knockdown diminished DMAS treatment efficiency, therefore DMAS induces apoptosis in-vitro in a NOXA dependent manner. Taken together, DMAS is a possible new cancer therapeutic for both chordoma and melanoma. However, further studies need to be conducted to fully understand DMAS induced effects and influenced pathways in both cancer types.