Chemopreventive Effect of Bitter Melon (Momordica charantia) Juice on Pancreatic Carcinogenesis in LSL‐Kras ^{G12D /+} ; p48 ^Cre/+

ABSTRACT

Herein, using the LSL‐Kras ^G12D/+ ; p48 ^Cre/+ transgenic mouse model [that recapitulates the full spectrum of human disease, progressing from early pancreatic intraepithelial neoplasia lesions to invasive pancreatic ductal adenocarcinoma (PDAC)], we determined the chemopreventive effect of long‐term (chronic) administration of Bitter Melon Juice (BMJ‐standardized lyophilized juice processed from the fruits of Momordica charantia ) against pancreatic cancer. Starting at 6 weeks of age, female LSL‐Kras ^G12D/+ ; p48 ^Cre/+ mice were subjected to BMJ intervention (oral gavage, dose: 200 mg/kg body wt., 5 days/week) for 35 weeks (study end: 41 weeks of age), and pathological and molecular changes in the pancreas were assessed. Results indicated that BMJ shifted the pancreatic tumor profile from moderately differentiated adenocarcinoma in controls towards a more heterogeneous profile enriched for well‐differentiated lesions indicating that prolonged exposure to BMJ bioactives results in a less aggressive phenotype. BMJ significantly reduced proliferative index (~24%) and induced a ~ 4‐fold increase in apoptosis in the pancreas. The effects on AMPK activation (~2‐fold increase) and decrease in the expression of [glucose (GLUT‐1) and lactate (MCT‐4) transporter levels (∼49%–69%,), NF‐κB/p65 (~40%), EMT marker‐Vimentin (~46%), fibrotic microenvironment marker (α‐SMA, ~29%) and Mucin‐1 (MUC‐1, ~45%)] indicate that BMJ modulates several interconnected pathways essential for PDAC growth and progression. Plasma proteomic profiling indicated that Fractalkine (CX3CL1), MIP‐3β (CCL19), MIP‐3α (CCL20), and SCF were decreased by BMJ, while Axl and TNF‐alpha were overexpressed in BMJ‐treated animals compared to positive controls. These results encourage further research into bitter melon compounds as a potential chemopreventive option for pancreatic cancer, especially for high‐risk groups.