Date of Award

2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

First Advisor

Pandey, Siyaram

Rights

CC BY-NC-ND 4.0

Abstract

Distinct characteristics, including decreased dependence on mitochondrial respiration and high levels of oxygen radicals, provide opportunities for cancer targeting. We have shown the compound pancratistatin (PST) to selectively induce apoptosis in cancers by mitochondrial targeting. However, its low availability in nature was limiting its preclinical development. Various PST analogues were synthesized to circumvent this limitation. In this dissertation, these analogues were screened and several had comparable or greater anti-cancer activity compared to PST. The analogue, SVTH-7, demonstrated the most potent anti-cancer activity, followed by SVTH-6 and -5 in vitro and in vivo. These compounds had greater efficacy than PST, 7-deoxyPST analogues, and multiple standard chemotherapeutics, and were found to induce apoptosis in cancer cells by acting on cancer cell mitochondria. Furthermore, the anti-cancer effects of PST analogues were enhanced when used with agents known to target cancer cell mitochondria and oxidative vulnerabilities, including tamoxifen, curcumin, and piperlongumine. Interestingly, functional complex II and III of the electron transport chain were required for SVTH-7 to inflict its pro-apoptotic effects on cancer cells, suggesting exploitation of a mitochondrial vulnerability by SVTH-7. Therefore, these findings demonstrate a novel approach to treat cancer by exploiting cancer cell mitochondria with PST analogues alone or in combination with other compounds. These PST analogues have high therapeutic potential and this work will lay the groundwork for the identification and characterization of distinct mitochondrial features of cancer cells.

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