Factor Quinolinone Inhibitor 1 (FQI1) is a novel anti-cancer compound, having shown efficacy against hepatocellular carcinoma (HCC) in multiple murine tumor models with no detectable toxicity at effective doses. FQI1 exerts its anti-proliferative activity against HCC cells by disrupting mitotic spindles and inhibiting the attachment between mitotic microtubules and kinetochores, thereby causing a mitotic arrest culminating in cell death or senescence. As patients suffering from HCC are challenged with a high mortality rate and HCC treatment options are limited, there is a dire need for developing new chemotherapeutics against HCC. In light of this, FQI1s are particularly promising for further development towards HCC chemotherapeutics.
Previous studies focused on the impact of FQI1 solely in mitosis. In this dissertation, I report on the cytoskeletal and morphological effects of FQI1 in interphase immortalized fetal hepatocytes and retinal pigment epithelial cells. I established that FQI1 drastically and rapidly reduces cell spreading and increases circularity in non-mitotic cells. These morphological phenotypes are preceded by a sudden breakdown of microtubules. FQI1 also decreases the range of locomotion of interphase cells and reduces their ability to close wound-gaps, supporting an impact of FQI1-induced microtubule breakdown on cell migration. The FQI1-induced microtubule destabilization activates the RhoA/ROCK contractility pathway, which plays a role in FQI1-mediated reduction of cell spreading. Taken together, I demonstrated that FQI1 interferes with microtubule-associated functions outside of mitosis that specifically regulate cell morphology, cell motility and contractility. As cancer cells rely on non-mitotic processes, most notably cell migration, to exert their malignancy, the findings presented here expand the potential of FQIs as effective and clinically successful anti-cancer compounds.
Finally, I document the potential utility of nanoparticles for intravenous delivery of lipophilic compounds to the liver, using FQI1 as an example. When FQI1 was encapsulated into expansile nanoparticles (eNPs), the eNPs were effectively internalized by hepatocytes in vitro and released FQI1 to exert growth inhibition. In addition, intravenously injected eNPs predominantly targeted the liver with minimal, if any, acute toxicity. As a proof of concept, I therefore show that lipophilic compounds including FQIs could be formulated with eNPs for treatment against liver diseases, including HCC. / 2022-11-01T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/43254 |
| Date | 02 November 2021 |
| Creators | Stoiber, Patrick Moritz |
| Contributors | Hansen, Ulla M. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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