Matching Items (3)
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- All Subjects: Quinone
- All Subjects: Temozolomide
- Creators: Hecht, Sidney
- Creators: Raghav, Nidhi
Description
It has been well established that mitochondria play a critical role in the pathology of Friedreich's Ataxia. This disease is believed to be caused by a deficiency of frataxin, which research suggests is responsible for iron sulfur cluster assembly. This incomplete assembly of iron sulfur clusters is believed to be linked with dysfunctional complexes in the mitochondrial respiratory chain, increased oxidative stress, and potential cell death. Increased understanding of the pathophysiology of this disease has enabled the development of various therapeutic strategies aimed at restoring mitochondrial respiration. This thesis contains an analysis of the biological activity of several classes of antioxidants against oxidative stress induced by diethyl maleate in Friedreich's Ataxia lymphocytes and CEM leukemia cells. Analogues of vitamin E α-tocopherol have been shown to protect cells under oxidative stress. However, these same analogues show various levels of inhibition towards the electron transport chain complex I. Bicyclic pyridinols containing a ten carbon substituent provided favorable cytoprotection. N-hydroxy-4-pyridone compounds were observed to provide little protection. Similarly, analogues of CoQ10 in the form of pyridinol and pyrimidinol compounds also preserved cell viability at low concentrations.
ContributorsJaruvangsanti, Jennifer (Author) / Hecht, Sidney (Thesis advisor) / Woodbury, Neal (Committee member) / Skibo, Edward (Committee member) / Arizona State University (Publisher)
Created2012
Description
Patients diagnosed with GBM, a highly migratory, heterogeneous, rapidly growing primary adult brain tumor are faced with a dismal prognosis. Recent research has shed light on cell-survival pathways that are induced after the DNA-damage response induced by TMZ. Autophagy, a major catabolic process meant to degrade damaged organelles and large misfolded proteins, has recently been shown to be activated by TMZ. However, a precise mechanism has not yet been determined. T98G cells treated with TMZ showed significant induction of unfolded protein response (UPR) markers such as GRP78, and LC3-II expression, indicating increased autophagosome formation. Additional experiments have used the autophagic inhibitor Bafilomycin A1 (Baf) to determine that autophagic flux is induced, supporting the conclusion that UPR induction by TMZ induces autophagy. Combination treatments with PI3K inhibitors PX-866 and BEZ235 with Baf as a means to shut down two critical mechanisms of GBM cell survival were explored in this research. PX-866 was found to inhibit autophagy, while BEZ235, was found to induce autophagy. The differential modulation of autophagy by these PI3K inhibitors offers new knowledge for utilizing more effective drug combinations to treat GBM and improve patient survival.
ContributorsSodoma, Andrej Michael (Author) / Anderson, Karen (Thesis director) / Hecht, Sidney (Committee member) / Nhan, Tran L. (Committee member) / School of Molecular Sciences (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Many natural and synthetic quinones have shown biological and pharmacological activity. Some of them have also shown anticancer activity. Ubiquinone (CoQ10) which is a natural quinone, is a component of the electron transport chain and participates in generation of ATP (adenosine triphosphate). Cellular oxidative stress is key feature of many neurodegenerative diseases such as Friedreich's ataxia, Alzheimer's disease and Parkinson's disease. The increased generation of reactive oxygen species damages cell membranes and leads to cell death. Analogues of ubiquinone in the form of pyrimidinols and pyridinols, were effective in protecting Friedreich's ataxia lymphocytes from oxidative stress- induced cell death. There were some structural features which could be identified that should be useful for the design of the analogues for cellular protection against oxidative stress. There are quinones such as doxorubicin, daunomycin and topopyrones which have anticancer activity. Here I evaluated topopyrone analogues which poison both topoisomerases I and II. The topopyrone analogues were lethal to human breast cancer cells, but these analogues were not as potent as camptothecin.
ContributorsRaghav, Nidhi (Author) / Hecht, Sidney M. (Thesis advisor) / Gould, Ian R (Committee member) / Williams, Peter (Committee member) / Arizona State University (Publisher)
Created2011