Pharmacological studies on phytochemicals for the treatment of prostate cancer
The aim of this thesis work is the investigation of the anticancer potential of selected phytochemicals including arglabin and 3-alpha-acetyloxy-tir-8,24-dien-21-oic acid (alpha-ATA(8,24)), isolated to chemical homogeneity by HPLC from Artemisia glabella and the oleo-gum resin extract of Boswellia serrata, respectively using prostatic carcinoma cell lines. Studies spanned to a systematic understanding of the mechanism of action of these compounds in killing the treatment-resistant human prostate cancer cells (PC-3 cells) using state of the art multi-analytical approach, employing XTT, flow cytometric, microscopic and western immunoblot analyses. Results showed that both phytochemicals can selectively inhibit the proliferation and also able to reduce the viability of PC-3 cells. Noteworthy, they are nontoxic to nonneoplastic human cells. Cell cycle analysis revealed an impediment of the cell cycle progression of PC-3 cells at G1 and G2 phases, and this is through altering the levels of cell cycle regulators. Furthermore, it was proved that the studied phytochemicals trigger apoptosis by activating caspase 3, which leads to loss of cell membrane asymmetry and DNA fragmentation in vitro. Interestingly, the applied in vivo model using PC-3 cells xenografted onto chorioallantoic membranes confirms their dual role in the inhibition of cancer cells proliferation and induction of apoptotic cell death. At the molecular level and prior to all biochemical signs of cellular dysfunction, arglabin and alpha-ATA(8,24), though through different mechanisms, inhibit the activity of mechanistic target of rapamycin (mTOR) signaling pathway, leading to the induction of cell cycle arrest, autophagy, lysosomal and mitochondrial destabilization, ROS production and apoptosis. Together, the presented data strongly suggest that arglabin and alpha-ATA(8,24) could be efficient lead compounds for therapeutics targeting diseases and disorders associated with aberration in mTOR signaling and apoptosis machinery.
Erstellung / Fertigstellung
Normierte SchlagwörterArglabin [GND]
Prostatic neoplasms [MeSH]