Date of Award

2015

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Molecular Biology

Abstract

Bladder cancer is a serious health concern among the older population, as it is responsible for thousands of deaths annually in the United States. Patients that are diagnosed with muscle-invasive disease have a 5-year survival rate of only 20 percent. Additionally, muscle-invasive disease has a high metastatic potential; half of all patients develop metastatic disease within 3 years. Patients with muscle-invasive disease are presented with few treatment options aside from surgery. The current standard of care is a chemotherapeutic combination therapy of cisplatin and gemcitabine. This therapy is highly toxic, and due to the high instance of co-morbidities in these patients, approximately half are unfit for therapy. An alternative combination of carboplatin plus gemcitabine allows for the inclusion of more patients, but is an inferior therapy. Development of an alternative treatment option is necessary.

Previous studies in the Foreman lab have shown a synergistic decrease in bladder cancer cell proliferation when the natural alkaloid emetine is combined with cisplatin in vitro. Here, we expanded these studies to demonstrate that the addition of emetine to both the cisplatin-gemcitabine as well as carboplatin-gemcitabine standard of care regimens resulted in an additive decrease in bladder cancer cell proliferation. Moreover, the addition of low dose emetine allows for up to a 10-fold decrease in effective dose of cisplatin or carboplatin. Treatment with this triple therapy appears to be inducing growth arrest in the cancer cells.

Hypoxia Inducible Factors (HIFs) are upregulated in response to low oxygen conditions, and regulate a wide range of genes responsible for giving tumor cells a selective advantage. HIF-α overexpression in bladder cancer corresponds to a poorer prognosis. This, as well as the concise regulation of HIFs, makes them an attractive target for anti-cancer therapy.

HIF-1α and HIF-2α are aberrantly upregulated under normoxia conditions in the invasive bladder cancer cell lines UMUC3, HT1376, and T24. Emetine is a know protein synthesis inhibitor at the micromolar level, but less is known about its actions at lower concentrations. We demonstrate here that low, nanomolar concentrations of emetine act to preferentially downregulate levels of HIF-1α and HIF-2α. Emetine appears to be acting via decreased HIF-1α protein synthesis. We hypothesize that emetine is acting in a similar manner on HIF-2α, but further work is necessary to confirm. This regulation of hypoxia signaling may act to decrease the cell’s selective advantage and proliferative potential.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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