Presenting Author Texas Tech University Health Science Center
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a survival rate of 10%. It is projected to be the second leading cause of cancer related deaths in USA by 2030. The therapeutic development against PDAC has been slow and chemotherapeutic resistance for available treatment options is a significant problem. Over the past few years, drug repurposing has shown promise as a fast, economic and reliable strategy to develop novel treatment options for most of the diseases. The repurposing of Remdesivir for COVID-19 is a recent example. Based on literature review, we screened multiple drugs for their anti-cancer efficacy and discovered potent anti-cancer activity of an anti-parasitic drug, MBO. We identified the anti-cancer effects of MBO in human PDAC cell lines AsPC-1, MiaPaCa-2, BXPC3, Panc-1 and SUIT-2. We also confirmed the effect of MBO to suppress colony formation in PDAC cell lines AsPC-1, MiaPaCa-2 and BXPC3. MBO induced apoptotic cell death in PDAC cell lines which was confirmed by Annexin V/APC analysis using flow cytometry. Importantly, through western blot analysis we identified that MBO inhibits the DARPP-32/β-catenin axis, an unexplored cellular signaling axis in PDAC. This identification is crucial since DARPP-32 is a novel protein which was recently identified to play a role in metastasis of PDAC. Pre-clinical efficacy of MBO was evaluated in an in vivo tumor model by subcutaneously injecting human PDAC cell line MiaPaCa-2 in the left flank of the mice. MBO significantly suppressed tumor growth by 80% at an oral dose of 5 mg/kg. To summarize, our results show MBO inhibits the growth of PDAC by inhibiting the novel DARPP-32/ β-catenin axis.
