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Morad, Samy (2010): Pharmacological studies of a novel inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway. Dissertation, LMU München: Faculty of Veterinary Medicine
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Abstract

The apoptotic mode of cell death (programmed cell death) is an active and defined process that plays an important role in the development of multicellular organisms and in the regulation and maintenance of cell populations in tissues under physiologic and pathologic conditions. Since dysregulation of apoptosis is associated with the progress of many diseases, induction of apoptosis is an interesting pharmacological target for the therapy of many diseases. Our study shows that the novel semisynthetic pentacyclic triterpenoid C-KβBA has a profound antiproliferative effect on different tumor cell lines and that it induces apoptosis of tumor cells in vitro and vivo. Previous studies have shown that the mammalian target of rapamycin (mTOR) is a key regulator for many cells activities, and that the perturbation of this signaling pathway is implicated in many diseases and metabolic disorders. Accordingly targeting the mTOR signaling pathway seems to be a promising therapeutic approach for the treatment of various diseases and metabolic disorders. We have shown in our study that C-KβBA downregulates the mTOR signaling pathway in vitro and vivo, which leads to the induction of cell cycle arrest in the G0 cell cycle phase as well as downregulation of the protein translation machinery. Together, the presented data strongly suggest that C-KβBA could serve as a lead compound for the development of novel treatment modalities for diseases and disorders associated with defects in the apoptosis machinery, or the mTOR signaling pathway, or both.