Date

2018

Department or Program

Biological Sciences

Primary Wellesley Thesis Advisor

Dora Carrico-Moniz

Additional Advisor(s)

Andrew Webb

Additional Advisor

Louise Darling

Abstract

In the United States, 40% of men and women will be diagnosed with cancer at some point in their lives. Of the possible diagnoses, pancreatic ductal adenocarcinoma (PDAC) is one the most devastating. Currently, the 5-year survival rate of PDAC is below 10%, one of the lowest for common carcinomas in the United States. The lack of effective chemotherapies for this disease is acute, leading to a search for new compounds derived from natural products. The Carrico-Moniz lab has developed isoprenylated coumarin derivatives as novel chemotherapies for PDAC. Several structure-activity relationship (SAR) studies have led to our current lead compound, DCM-MJ-I-21. Studies with our lead compound in 2D cytotoxicity assays show that DCM-MJ-I-21 is selectively cytotoxic against PANC-1 cells under nutrient-deprived conditions. However, because 2D assays cannot fully capture a 3-dimensional in-vivo tumor environment, studies with PANC-1 in 3D spheroid cultures were conducted. These initial studies found that even in 3D spheroids, DCM-MJ-I-21 is cytotoxic in nutrient deprived media. In this study, we began by validating these initial results, finding that while our lead compound is effective against PANC-1 spheroids, there exists variability in cytotoxicity. Next, the efficacy of DCM-MJ-I-21 was evaluated in 2D and 3D assays with another PDAC cell line, BxPC-3. These studies found that our lead compound has reduced cytotoxicity against BxPC-3 spheroids under nutrient deprived conditions compared to PANC-1 spheroids. Qualitative analysis also shows that BxPC-3 spheroids decrease in diameter after treatment in nutrient-deprived media and increase in diameter after treatment in nutrient-rich media. These findings are contrary to the trends seen in PANC-1 spheroids and may help in understanding the mechanisms underlying the differences in cytotoxicity found between the two cell lines. Future studies with other PDAC cell lines such as Capan-2 will further elucidate the limits of DCM-MJ-I-21 in treating the diverse population of PDAC. This study confirms the effectiveness of DCM-MJ-I-21 against PANC-1 spheroids and demonstrates that this is not necessarily true in other PDAC cell lines.

Available for download on Tuesday, April 25, 2023

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