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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Therapeutic Modulation of Cancer Metabolism with Dichloroacetate and Metformin

Ward, Nathan Patrick 07 April 2017 (has links)
The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin’s reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in the VM-M3 model of GBM. We demonstrated that metformin potentiated DCA-induced superoxide production and that this was required for enhanced cytotoxicity towards VM-M3 cells with the combination. Similarly, rotenone enhanced oxidative stress resultant from DCA treatment and this too was required for the noted augmentation of cytotoxicity. Adenosine monophosphate kinase (AMPK) activation was not observed with the concentration of metformin required to enhance DCA activity. Moreover, addition of an activator of AMPK did not enhance DCA cytotoxicity, whereas an inhibitor of AMPK heightened the cytotoxicity of the combination. We also show that DCA and metformin reduce tumor burden and prolong survival in VM-M3 tumor-burdened mice as individual therapies. In contrast to our in vitro work, we did not observe synergy between DCA and metformin in vivo. Our data indicate that metformin enhancement of DCA cytotoxicity is dependent on complex I inhibition. Particularly, that complex I inhibition cooperates with DCA-induction of glucose oxidation to enhance cytotoxic oxidative stress in VM-M3 GBM cells. This work supports further investigation and optimization of a DCA/metformin combination as a potential pro-oxidant combinatorial therapy for GBM.
2

Metagenom-Technologie zur Wirkstoffsuche sowie Untersuchungen der Iromycine aus Streptomyces sp. / Metagenome Technology for Drug Discovery and Studies of the Iromycins from Streptomyces sp.

Surup, Frank 03 July 2007 (has links)
No description available.

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