Date of Award

12-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Healthcare Genetics

Advisor

Eggert, Julia A

Committee Member

Chen , Chin-Fu

Committee Member

Dye , Cheryl J

Committee Member

Larcom , Lyndon L

Abstract

Chemotherapy is a widely used treatment for cancer, with significant side effects including cognitive impairments that affect patients' quality of life. Red raspberries are known to inhibit growth of cancer cells with recent research suggesting the ability to also protect neurons. If this protective ability can be confirmed, red raspberry may emerge as a promising natural intervention for cognitive impairments associated with chemotherapy. In addition, many studies have linked cognitive functions to epigenetic mechanisms postulating that transient reprogramming of epigenetic mechanisms, such as DNA methylation, is required for some basic neuronal/cognitive functions.
The objective of this dissertation is to study the effects of in vitro digested and in vivo human metabolized red raspberry on doxorubicin chemotherapy initiated neurotoxicity in nerve growth factor induced PC12 pheochromocytoma neuronal cells, and explore the underlying epigenetic DNA methylation changes associated with this process.
Primary results are summarized as: 1) minute amounts, as low as 0.001μ of doxorubicin reduced the metabolic activity of nerve growth factor induced PC12 neuronal cells, exibiting neurotoxicity; 2) in vitro digested red raspberry counteracted the toxic effects of doxorubicin chemotherapy on the metabolic activity and neurite growth of nerve growth factor induced PC12 neuronal cells; 3) participants' plasma after red raspberry consumption showed positive effects on metabolic activity of nerve growth factor induced PC12 neuronal cells treated with doxorubicin chemotherapy; 4) DNA methylation pattern of FOS gene for nerve growth factor induced PC12 neuronal cells treated with doxorubicin was different from the control and in vitro digested red raspberry treated cells. Possible explanations for these results are discussed.
This dissertation research contributes to a better understanding of neurotoxicity due to doxorubicin chemotherapy and the neuroprotection of in vitro digested and in vivo human metabolized red raspberry at the cellular and epigenetic level. This work provides evidence for future preliminary clinical trials investigating natural red raspberry consumption as an intervention for cognitive impairments in cancer patients receiving doxorubicin chemotherapy.

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