Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Mikulcic, M.
15d-PGJ2 – a plausible therapeutic agent against osteosarcoma
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 85
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Hrzenjak Andelko
- Malle Ernst
- Sattler Wolfgang
- Altmetrics:
- Abstract:
- Osteosarcoma (OS) is the most often occurring type of bone cancer. It mainly affects children and adolescents and still has a very limited choice of therapy. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a cyclic prostaglandin originating from the arachidonic acid. It is naturally present in the human body and has been known for its remarkable anti-inflammatory as well as anti-cancer effects. In this study, we have investigated the effect of 15d-PGJ2 on OS cells and the molecular mechanisms that underlie these effects. The cell lines used were of a human origin and osteoblast-like characteristics (U2-OS and Saos-2). The effect of 15d-PGJ2 on the OS cell lines was explored through observing the effect of the compound on cell survival, cell proliferation, cell motility and tumorigenic capability of the cells, showing a marked decrease of all of the aforementioned tumor cell characteristics. H2DCFDA was used to determine the effects of 15d-PGJ2 on the intracellular ROS levels, which in turn showed a significant time dependent increase in ROS production. Protein expression analyses via immunoblotting revealed a 15d-PGJ2-triggered time-dependent increase in MAPK activation (pp38, pJNK and pERK1/2), though the cytoprotective proteins showed mainly a steady decline in their expression. In parallel, immunoblotting and Annexin V/PI staining revealed the presence of strong apoptotic events within both OS cell lines post-15d-PGJ2 treatment. The ex ovo CAM model was used to study the effect of 15d-PGJ2 on the OS cells growth capability, showing a pronounced impact on the onplant size compared with the control cells. These findings were also confirmed by hematoxylin/eosin as well as Ki-67 immunohistochemical stainings. Lastly, we investigated whether a 15d-PGJ2 structural analogue, 9,10-dihydro-15d-PGJ2, could mimic the cytotoxic impact that the original compound had on the OS cells. However, our findings suggest that the change in structure proved to be relevant as the analogue failed to cause any effect in both cell lines. Taken together, our data suggest that 15d-PGJ2 has the potential of playing a prominent role as an anti-OS natural compound.