Date

2017

Department or Program

Biological Chemistry

Primary Wellesley Thesis Advisor

Dora Carrico-Moniz

Additional Advisor(s)

Andrew C. Webb

Additional Advisor

Donald E. Elmore

Additional Advisor

Ismar Volic

Abstract

Pancreatic cancer is one of the most aggressive and lethal solid malignancies with more than 50,000 patients in 2016 and <5% 5-year survival rate. It owes aggressiveness in part to the unusual ability of cells to survive under nutrient deprivation for prolonged periods of time. The mechanisms underlying this property have recently become valuable biochemical targets for the potential treatment of pancreatic cancer. Angelmarin (isolated from a medicinal plant, Angelica pubescens) exhibits preferential cytotoxicity to pancreatic cancer cells under nutrient deprivation. Our lab has synthesized multiple coumarin-based derivatives of Angelmarin, identifying DCM-MJ-I-21 as the current lead, with LC50 value of 4μM under nutrient deprivation and no activity in the presence of nutrients. This compound has been well characterized in 2D cell culture in vitro assays, however, these data may not be predictive of its behavior in vivo due to multiple differences between the 3D in vivo environment, and 2D environment of in vitro assays. The present study utilized 3D spheroid cultures to characterize DCM-MJ-I-21 under more in vivo-like conditions. A 3D spheroid cytotoxicity assay was developed and optimized specifically for the purposes of DCM-MJ-I-21 investigation in PANC-1 spheroids. Next, the efficacy of the compound was compared between 2D and 3D cultures, indicating that DCM-MJ-I-21 retains preferential activity under nutrient deprivation in 3D, causing spheroid structural disintegration even at the lowest concentration. Finally, a preliminary comparative study of DCM-MJ-I-21, 5-FU, and VP-16 in 3D showed that DCM-MJ-I-21 was superior to both, 5-FU and VP-16 under nutrient deprivation conditions even in 3D. Further studies are required to fully investigate the properties of DCM-MJ-I-21, chemotherapeutics as well as the combination therapies in 3D spheroid cultures, and the present study provides a solid foundation for these experiments with an optimized 3D spheroid cytotoxicity assay and the preliminary data.

Available for download on Wednesday, April 20, 2022

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