Date of Award

1-1-2012

Document Type

Campus Access Dissertation

Department

Biomedical Science

First Advisor

Swapan K Ray

Abstract

Neuroblastoma is a tumor of sympathetic nervous system origin and the most common extracranial heterogenous solid tumor of childhood affecting primarily infants. Despite multimodal conventional therapeutic approaches including chemotherapy, radiation therapy, immunotherapy, and neurosurgery, the survival rate of children affected with advanced stage neuroblastoma remains significantly low. Therefore, there is an urgent need to develop innovative therapeutic approaches to inhibit the growth of human malignant neuroblastoma. The concept of using `combination therapy' for treatment of cancer has gained considerable interest in recent years, where two or more anti-cancer drugs acting with different molecular mechanisms can be employed at suboptimal doses to control the tumor growth. The major advantages of using combination therapy are to minimize the toxicity to normal tissues and to overcome drug resistance. This study is focused on developing a novel combination of drugs targeted towards various cellular processes such as apoptosis, angiogenesis, autophagy, and differentiation for controlling growth of neuroblastoma cells.

In the first treatment strategy, we explored the efficacy of a combination of the inhibitor of the anti-apoptotic protein Bcl-2 HA14-1 (HA) and the isoflavonoid genistein (GST) in human malignant neuroblastoma cells. Results showed that combination therapy synergistically induced apoptosis by activating caspase cascade and down regulating survival and oncogenic factors in neuroblastoma cells. The second strategy was focussed on using the anti-angiogenic compound SU5416 (SU) in combination with the green tea polephenolic compound (−)-epigallocatechin-3-gallate (EGCG). Angiogenesis is a pre-requisite for tumor progression and metastasis. Our data showed that a combination of SU5416 and EGCG inhibited pro-angiogenic molecules and induced cell cycle arrest to inhibit neuroblastoma cell proliferation. A third strategy explored the role of autophagy inhibition as an important tool to induce apoptosis in neuroblastoma cells, where a combination of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) and the flavonoid apigenin (APG) suppressed starvation-induced autophagy and triggered apoptosis. In our final combination strategy, we induced cellular differentiation in immature neuroblastoma cells by treating with a combination of 4-HPR and the Bcl-xL inhibitor (2,3-DCPE) and thereby making them more susceptible to apoptosis. Taken all the results into consideration, this study indicates that combination therapy can very effectively modulate the molecular components of cells to induce the apoptosis and inhibit neuroblastoma tumor progression.

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