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Type of Document Dissertation Author McHenry, Peter Ryan Author's Email Address pmchenr2@nd.edu URN etd-10202008-103712 Title Elucidating the mechanism of action of the novel marine macrolide iejimalide Degree Doctor of Philosophy Department Biological Sciences Advisory Committee
Advisor Name Title Martin Tenniswood Committee Chair Edward Hinchcliffe Committee Member JoEllen Welsh Committee Member Paul Helquist Committee Member Keywords
- ROS
- cell cycle
- natural product
- intracellular pH
- Q-PCR
- flow cytometry
Date of Defense 2008-09-19 Availability unrestricted Abstract Iejimalides are a novel family of marine macrolides shown to be active against cancer cells in vitro that inhibit vacuolar H+-ATPase (V-ATPase) activity in osteoclast cells. Iejimalide B (Iej B) arrests cells in G1- or S-phase of the cell cycle and induces apoptosis in a cell-line specific manner. Multiple genes in the p53 cell cycle arrest/cell death pathway are induced upon treatment by Iej B, suggesting that apoptosis is mediated by a p53-dependent mechanism. Iej A and B prevent acidification of lysosomes and depolarize mitochondria and induce reactive oxygen species production in a time-dependent manner. Mitochondrial depolarization is augmented by cyclosporin A treatment, suggesting an autophagic response to Iej B. Iej B is not an inhibitor of ATP synthase (F-ATPase) as measured by oxygen consumption of rat heart mitochondria in the presence of ADP. At least one target of ATM/ATR phosphorylation is de-phosphorylated in PC-3 prostate cancer cells in the presence of Iej B, suggesting a block in cell cycle progression at the intra-S-phase checkpoint. This arrest is irreversible in the aggressive PC-3 cell line. Iej A/B induce S-phase arrest in several cell lines regardless of p53 status, suggesting that this effect of Iej A/B is p53-independent. CHO-A8 cells, which re-duplicate their centrioles under conditions of prolonged S-phase arrest, maintain normal centriole numbers when arrested by Iej A/B. Iejimalides appear to have unique effects on cancer cells and should be further developed as anti-cancer agents.Files
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