Defense Date

2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemical Biology

First Advisor

Nicholas Farrell

Second Advisor

John Ryan

Abstract

The work discussed here is divided into two projects. The first project involves the interactions between antidepressants and the platinum based chemotherapeutics while the second project begins to investigate possible implications of a recently discovered uptake mechanism for positively charged platinum drugs. Gaining understanding of the interactions between antidepressants and platinum-based chemotherapeutics is important due to the frequency with which they are prescribed together. Although using a combination regimen of antineoplastics is beneficial to the patient, not all drug interactions are. For instance, many of the serotonin reuptake inhibitors have been shown to decrease the efficacy of tamoxifen. Desipramine, a tricyclic antidepressant used to treat neuropathic pain, has been shown to increase the cytotoxicity of cisplatin, oxaliplatin and carboplatin in the human colon carcinoma cell line, HCT116 wt. To study this interaction, the cell line specificity as well as the drug specificity with regard to both the platinum-based chemotherapeutic and the antidepressant were investigated. The data show that the effect is both cell line specific as well as drug specific with respect to both types of drugs. To elucidate the mechanism behind the alteration in cytotoxicity of the platinum drugs, the effect of p53 status was investigated. A reduction of the effect is observed in the absence of p53, suggesting that there is a p53 dependent mechanism as well as a p53 independent mechanism. The tricyclic antidepressants and fluoxetine are known to be calmodulin inhibitors. Calmodulin inhibition mirrored some of the effects seen with the antidepressants suggesting that calmodulin inhibition might also play a role in the mechanism. The second project is based on the discovery that heparan sulfate proteoglycans mediate the uptake of positively charged platinum complexes. Heparan sulfate proteoglycans are important in cell-cell as well as cell-extracellular matrix adhesion. In cancer, heparanase, the enzyme that cleaves heparan sulfate, is over expressed creating a pro-angiogenic and pro-metastatic state. This work demonstrates that the positively charged platinum complexes can inhibit heparanase activity by binding to the substrate (heparan sulfate proteoglycans). This suggests that this class of drugs may have the capacity to be anti-angiogenic and anti-metastatic as well as cytotoxic.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

September 2012

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