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ANTI-NEUROBLASTOMA EFFECTS OF RETINOIC ACID,
INTERACTIONS WITH CHEMOTHERAPEUTIC AGENTS,
AND REGULATION OF MYCN EXPRESSION
by
Michael Daniel Hadjidaniel
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
May 2009
Copyright 2009 Michael Daniel Hadjidaniel
Object Description
| Title | Anti-neuroblastoma effects of retinoic acid, interactions with chemotherapeutic agents, and regulation of MYCN expression |
| Author | Hadjidaniel, Michael Daniel |
| Author email | hadjidan@usc.edu; mhadjidaniel@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pathobiology |
| School | Keck School of Medicine |
| Date defended/completed | 2009-03-09 |
| Date submitted | 2009 |
| Restricted until | Restricted until 14 Apr. 2011. |
| Date published | 2011-04-14 |
| Advisor (committee chair) |
Reynolds, C. Patrick Press, Michael F. |
| Advisor (committee member) | Yang, Allen S. R. |
| Abstract | Neuroblastoma is a childhood neuroendocrine tumor, which originates from sympathetic nervous system precursors. The major indicator of poor prognosis for the disease is amplification of MYCN, a gene directly related to neuronal development. The developmental origins of the disease give it a highly heterogeneous character and biology, one that ranges from spontaneous regression and differentiation to aggressively recurring disease. The neuronal attributes of neuroblastoma and its capacity to differentiate have been successfully utilized in disease treatment by incorporating the differentiating agent 13-cis-retinoic acid (13-cis-RA) in the standard of care. Despite the fact that 13-cis-RA treatment in the context of minimal residual disease (MRD) has improved event free survival, the outcome for high-risk neuroblastoma patients is still bleak, with approximately 50 % of patients succumbing to the disease. Such is the nature of the high-risk disease that novel combinations of therapy are required to battle its recurrence. In this body of work, we investigate the interactions of 13-cis-RA with other chemotherapeutic agents, in neuroblastoma cell lines. We first describe an antagonistic relationship between 13-cis-RA and several chemotherapeutic compounds, currently in use for neuroblastoma treatment. More specifically we show that the retinoid antagonizes apoptotic cell death in response to cytotoxic chemotherapy, by inhibiting the mitochondrial apoptotic pathway. Our studies also examine the effects of combining the differentiating agent 13-cis-RA with the Histone Deacetylase inhibitor (HDACi) vorinostat (SAHA). Our data show the combination achieves long-term growth inhibition in a panel of several neuroblastoma cell lines, an effect marked by a distinct downregulation in MYCN protein levels.; Finally, given the importance of MYCN in neuroblastoma biology, and its relation with RA-induced growth arrest, this study explores whether DNA methylation at the MYCN promoter contributes to the long-term silencing of this gene in response to RA. |
| Keyword | neuroblastoma; retinoic acid; cytotoxic chemotherapy; antagonism; SAHA; MYCN |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2086 |
| Rights | Hadjidaniel, Michael Daniel |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Hadjidaniel-2681 |
| Archival file | uscthesesreloadpub_Volume48/etd-Hadjidaniel-2681.pdf |
Description
| Title | Page 1 |
| Full text | ANTI-NEUROBLASTOMA EFFECTS OF RETINOIC ACID, INTERACTIONS WITH CHEMOTHERAPEUTIC AGENTS, AND REGULATION OF MYCN EXPRESSION by Michael Daniel Hadjidaniel A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PATHOBIOLOGY) May 2009 Copyright 2009 Michael Daniel Hadjidaniel |
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