Access Type

Open Access Dissertation

Date of Award

1-1-2010

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Nutrition and Food Science

First Advisor

Smiti V. Gupta

Abstract

SYNERGISTIC EFFECTS OF GARCINOL AND GEMCITABINE IN ENHANCING THERAPEUTIC EFFICACY IN PANCREATIC ADENOCARCINOMA CELLS AND ITS EFFECT ON MICRORNA PROFILE

By

MANSI PARASRAMKA

ADVISOR: DR. SMITI V. GUPTA

MAJOR: NUTRITION AND FOOD SCIENCE

DEGREE: DOCTOR OF PHILOSPHY

Human Pancreatic Cancer (PaCa) is one of the most hostile and fourth leading cause of cancer deaths in the United States. Current standard chemotherapeutic agent for advanced PaCa is gemcitabine, a cytotoxic nucleoside analogue which results in modest response due to high degree of inherent and acquired chemo resistance. Forthcoming evidence strongly supports that non-nutritive food components have therapeutic benefits attributable to pleiotropic effects including inactivation of survival signaling and simultaneously activating multiple death pathways in tumors. Garcinol from the plant Garcinia indica have exhibited anti-inflammatory, antioxidant, and anticarcinogenic activity in several cancer types including colon, tongue, breast, skin and liver. This study aims to test 1) therapeutic efficacy of garcinol against PaCa (BxPC-3 and Panc-1) cells 2A) its role in dietary interactions with curcumin and 2B) drug sensitization with gemcitabine and 3) identify microRNA targets in PaCa cells on treatment with garcinol and gemcitabine. The activity of transcription factor nuclear factor - ?;B (NF-?;B) has long been associated with pancreatic tumor growth and angiogenesis, playing an important role in cell survival, chemotaxis and inflammation. Angiogenesis, a very crucial process in tumorigenesis requires the interplay between NF-?;B with other proangiogenic and antiangiogenic factors such as vascular endothelial growth factor (VEGF), Interleukin-8 (IL-8) and matrix metalloproteinase (MMP-9). We hypothesize that molecular targeting of critical signaling pathways (NF- ?;B, VEGF, IL-8 and MMP-9) with gemcitabine in combination with garcinol may improve efficacy by enhancing the signaling response to treatment. Emerging evidence suggests that microRNAs regulate carcinogenesis by controlling gene expression either by their tumor suppressor or oncogenic abilities. We observed that garcinol individually or in combination with curcumin or gemcitabine exhibited potent anticancer abilities in PaCa cells by down-regulating cancer promoting pathways and up-regulating the tumor suppressor mechanisms. Decreased NF- ?;B activity was observed in both cell lines in combination treatment along with significantly reduced levels of angiogenic factors MMP-9, VEGF, IL-8 and PGE2. We also performed target analysis after treatment to identify those microRNAs that regulate several cancer signaling pathways. We observed a downregulation in expression of oncogenic miRNA - 21, - 196a and - 495 along with upregulation of tumor suppressor miRNA - 638 and - 453 on treatment with garcinol alone or in combination with gemcitabine. Overall, our results demonstrate that garcinol and gemcitabine in combination have higher efficacy in modulating levels of various factors involved in tumorigenesis and have potential in chemotherapy against PaCa.

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