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Grant Abstract: Molecular mechanisms of bitter melon juice efficacy against pancreatic cancer

Grant Number: 5R01CA195708-02
PI Name: Agarwal
Project Title: Molecular mechanisms of bitter melon juice efficacy against pancreatic cancer

Abstract: The central focus of the ongoing funded grant R01 CA195708 is to examine and establish the efficacy and molecular mechanisms of bitter melon juice (BMJ) against pancreatic cancer (PanC) in various pre-clinical cancer models. The specific aims are to further: I) define the mechanisms by which BMJ targets metabolism and affects AMPK-mediated growth inhibition and apoptosis in PanC cells; II) define the mechanisms by which BMJ targets Notch and Hedgehog pathways and effectively inhibits cancer stem cell population in PanC; and III) establish BMJ molecular mechanisms defined in specific aims I and II in PDX1-Cre; LSL-KRASG12D mouse model. In specific aim I, together with mechanistic studies in cell culture, we have also proposed to examine the effect of BMJ feeding on PanC tumor metabolism by FDG-PET imaging, and detailed analyses of tumor tissues for metabolites by 1H- and 31P-NMR. Overall, in the parent grant our primary focus is to determine BMJ’s effects on PanC cells metabolism. However, BMJ feeding could also modulate metabolism in the animal body which could directly or indirectly impact BMJ efficacy against PanC tumors. Such studies are not proposed in the parent grant and form the basis of this supplement. In a pilot preliminary study, we analyzed the effect of BMJ on metabolites following its treatment in nude mice, by utilizing the plasma samples from a recently published study showing the strong effect of BMJ feeding in inhibiting MiaPaCa-2 xenograft growth in nude mice without any toxicity. The results of this efficacy study were part of preliminary data in the parent grant application. From this study, plasma samples from control and BMJ treated mice (n=3) were processed, and metabolites extracted and analyzed by liquid chromatography mass pectrometry
(LCMS) on a quadrupole time-of-flight (QTOF) mass spectrometer. Overall, approximately 5,000 metabolites were detected and analyzed. Importantly, there was a clear difference in the total ion chromatogram (‘control mice’ versus ‘BMJ treated mice’), and about 149 metabolites (p-value < 0.05 and fold-change > 2) were significantly different between control and BMJ treated mice. These preliminary results clearly established the feasibility of metabolites analysis in plasma following BMJ feeding, and could be useful in the proposed timecourse xenograft experiment (in the parent grant) to identify BMJ’s effect on metabolism/metabolites, and
whether that is correlated with its effect on PanC tumor growth. We have also proposed to examine BMJ effect on metabolism in healthy mice without PanC tumors. Overall, this additional information would strongly complement the earlier proposed experiment analyzing BMJ effects on PanC cells metabolism. Human Health Relevance: Bitter melon juice is widely consumed as an herbal dietary supplement for its preventive and therapeutic effects against several diseases. It has been even evaluated in clinical trials for its anti-diabetic
effects; therefore, the outcomes of the supplemental studies together with the parent grant would have significant clinical impact on the rationalized use of BMJ in human health and

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