Document Type

Dissertation

Date of Degree

Spring 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmacology

First Advisor

Raymond J. Hohl

Abstract

Schweinfurthins are intriguing natural product chemotherapeutics due to their potent yet selective activity and their unknown mechanism of growth inhibition in cancer. Much progress has been made in characterizing the intracellular effects of the schweinfurthins since they were first isolated from Macaranga schweinfurthii in 1986. Here, the L-type calcium channel and P- glycoprotein (Pgp) inhibitor verapamil has been found to enhance schweinfurthin- induced growth inhibition. Verapamil induces an increase in the intracellular concentration of a fluorescent schweinfurthin. However, the synergistic relationship between the schweinfurthins and verapamil is complex and not obvious in that verapamil fails to increase the intracellular concentration of a schweinfurthin analogue that is a known substrate of Pgp. Schweinfurthins are also found to induce alterations to cholesterol homeostasis by increasing the expression of the cholesterol efflux pump ABCA1 in an apparent liver X receptor- independent fashion. In addition, schweinfurthin treatment blunts epidermal growth factor downstream activation and phosphorylation of Akt. Lastly, a schweinfurthin-resistant cell line has been created and characterized for resistance to schweinfurthin-induced growth inhibition. The variety of intracellular effects characteristic of schweinfurthin treatment described here provide mechanistic framework for identifying the potential target and mechanism of growth inhibition for the schweinfurthins.

Public Abstract

Drugs designed to treat cancer extend the lives of countless patients diagnosed with cancer each year. Certain cancer types, including brain cancers, are difficult to treat due to a lack of effectiveness of current cancer drugs. Therefore, there is a need to discover new types of drugs to treat brain cancer. The schweinfurthins are a new type of cancer drug class that display effectiveness against brain cancer. Investigations into how the schweinfurthins are effective against brain cancer are warranted in order to develop the schweinfurthins into a cancer drug prescribed by doctors and used by patients in the clinic. Research presented herein has identified a range of effects that occur inside brain cancer cells that are treated with schweinfurthins. When brain cancer cells are treated with schweinfurthins, the ability to regulate growth is altered. Schweinfurthins have been found to decrease activation of growth signals normally present in brain cancer cells. Furthermore, another drug called verapamil has been found to enhance the ability of the schweinfurthins to inhibit growth of brain cancer cells. Results presented here outline a variety of effects that the schweinfurthins elicit inside brain cancer cells. This outline is important and provides a reference to use once the exact mechanism of the schweinfurthins is discovered.

Keywords

publicabstract, ABCA1, cancer, EGFR, P-glycoprotein, schweinfurthin, verapamil

Pages

xi, 98 pages

Bibliography

Includes bibliographical references (pages 92-98).

Copyright

Copyright 2015 Ryan Michael Sheehy

Included in

Pharmacology Commons

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