Access Type

Open Access Dissertation

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Nutrition and Food Science

First Advisor

SMITI V. GUPTA

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive form of pancreatic cancer with low survival rates partly due to late diagnosis and poor treatment outcomes. The use of chemotherapy drug, gemcitabine alone often provides minimal benefits. This study explored the in vivo effect of oil palm phenolics (OPP), a water-soluble extract from oil palm in transgenic mouse model of PDAC and its combination with gemcitabine. Administration of 5% dietary OPP was found to be non-toxic in non-PDAC controls. Compared to single agent therapy with either OPP or gemcitabine, OPP-gemcitabine combination showed a superior benefit with profound synergistic effect both as chemotherapeutic and chemopreventive agent evident in halted tumor and cyst growth, as well as lowered high grade precursor lesion count. Favorable regulation of several tumorigenesis markers through immunohistochemistry (S100P and SMAD4) and real-time PCR (Notch1, MMP9 and CCND1) that was partially displayed by OPP but was more significant with the combinatorial therapy has provided an insight on the molecular targets responsible for the anticancer effect of OPP and OPP-gamcitabine combination . Using multivariate analysis software, SIMCA-P+, discrimination in urinary 1H NMR metabolomic profiles between groups was revealed. Metabolite profiling has identified decreased levels of alanine, creatinine, succinate and taurine following intervention with OPP and its combination with gemcitabine. Metabolomic profiles were shown to be strongly correlated with Notch1 and MMP9 expression, also with total precursor lesion count following regression analyses. Finally, pathway analyses by MetaboAnalyst software, based on the information from regression analyses revealed that taurine, which involved in taurine and hypotaurine metabolism plays a major role in the anticancer effect exhibited by both interventions of OPP alone and OPP-gemitabine combination. Collectively, OPP as a single agent exhibited a milder therapeutic effect than the use of OPP in combination with gemcitabine which displayed superior advantage. This demonstrates the potential benefit of dietary OPP as part of combinatorial therapy against progression of PDAC.

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