Access Type

Open Access Dissertation

Date of Award

January 2012

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Nutrition and Food Science

First Advisor

Smiti Gupta

Abstract

Non-small cell lung cancer (NSCLC) is most hostile and leading cause of cancer deaths in the United States. Clinical data has demonstrated that 30 % of NSCLC patients have increased Notch activity and 10% of NSCLC have gain-of-function mutation on Notch-1 gene. Our data demonstrated that delta-tocotrienol could inhibit NSCLC cells proliferation, invasion and induce apoptosis by down-regulation of the Notch-1 signaling pathway. Using microRNA microarray and microRNA transfection, our findings further suggest that delta-tocotrienol is a non-toxic activator of miR-34a which can inhibit NSCLC cell proliferation, induce apoptosis, and inhibit invasion. Last but not the least, We observed that delta-tocotrienol individually or in combination with cisplatin exhibited potent anticancer abilities in NSCLC cells by down-regulating oncogenic pathways such as Notch-1 and NF-ĸB pathways and up-regulating the tumor suppressor pathways such as Bcl-2, caspase-3. Decreased NF- κB activity was observed in both cell lines in combination treatment along with significantly reduced levels of angiogenic factors MMP-9, VEGF thus offering a potential starting point for the design of novel anticancer agents. Overall, our results suggest that delta-tocotrienol could be a promising approach for designing tailored novel combination therapies for the treatment of human NSCLC.

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