Pancreatic cancer (PC) is an aggressive disease with poor prognosis because it is usually diagnosed at an advanced stage and current treatments are ineffective. Sesquiterpene lactones (SL) are natural products with established anti-cancer properties. The central hypothesis of this dissertation is that SLs exhibit their cytotoxic activity on cancer cells via inhibition of the NF?B pathway and pathways mediating redox homeostasis in a manner that can be utilized to help treat pancreatic cancer effectively.
Dimethylaminoparthenolide (DMAPT), a first-generation SL, was studied in combination with Actinomycin-D in efforts to identify a drug combination effective against Panc-1 human PC cells. However, the additive-synergistic combinations that were identified were not effective enough to warrant further development. First-generation SLs were ineffective for killing Panc-1 cells in a clinically relevant dose range. Second-generation, dimeric SLs were developed to be more potent in overcoming this ineffectiveness.
JVM-355 and its water-soluble analog JVM-355C were the most toxic dimeric SLs when tested with glioblastoma and PC cell lines. As anticipated, JVM-355 inhibited phosphorylation of the main components of the NFκB pathway in Panc-1 cells: i.e. the IKK complex, IκB and p65. Inhibition of MyD88, an adapter protein, and TAK-1, an upstream kinase responsible for phosphorylating IKKβ, was also observed. JVM-355 was also screened against three normal cell lines and lacked selectivity, being cytotoxic to both cancer cells and normal cells.
Thioredoxin reductase, thioredoxin-1 and the glutathione/oxidized glutathione ratio were reduced in a dose-dependent manner by JVM-355 in Panc-1 cells. It was also observed that inhibition of these oxidative stress pathways by JVM-355 was independent of its NFκB inhibitory activity. To accomplish tumor-localized delivery of JVM-355 while minimizing normal tissue toxicity, liposomes of the water-soluble JVM-355C analog were prepared. Methods of targeted and controlled delivery of liposomes, such as using light or radiation to release the drug in tumors, and to enhance accumulation of liposomes in the tumor with irreversible electroporation, were discussed.
In conclusion, JVM-355 acts by independent inhibition of NF?B and redox stress in Panc-1 cells. This study provides insight into how the dimeric SL, JVM-355 and its water-soluble analog act, and identifies potential targets for further drug development of anti-PC agents.
|Advisor:||Crooks, Peter A., Borrelli, Michael J.|
|Commitee:||Biris, Alexandru, Breen, Philip, Hendrickson, Howard|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Pharmaceutical sciences|
|Keywords:||Glutathione, Nfκb, Pancreatic cancer, Sesquiterpene lactones, Thioredoxin|
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