Publication Date
2024
Document Type
Thesis
Committee Members
Michael G. Kemp, Ph.D. (Advisor); Yong-jie Xu, M.D., Ph.D. (Committee Member); Ravi P. Sahu, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Cisplatin is an effective chemotherapeutic agent that is used to treat lung, breast, esophageal, ovarian, and pancreatic cancers. Despite being effective in treating a wide variety of cancer types, its cytotoxicity to off-target healthy tissues restricts its therapeutic application. The platinum atom of cisplatin interacts with DNA and results in the formation of inter-and intra-strand crosslinks, which are often referred to as DNA adducts. These adducts are mutagenic and potentially lethal to cells. The sole pathway for cells to excise intra-strand cisplatin-DNA adducts from the genome is through nucleotide excision repair. The fate of unrepaired DNA adducts is not understood fully. However, using a combination of differential centrifugation and DNA immunoblotting, we have detected cisplatin adduct-containing damaged DNA associated with small extracellular vesicles (SEVs) that are released into the cell culture medium. Moreover, the inhibition of caspase signaling blocks this release. Our observation that this response holds with multiple different cancer cell lines (U2OS, HeLa, HEK293, A375) suggests that it is a general phenomenon of cancer cell response to cisplatin. Because SEVs are involved in intercellular communication and can transmit their contents throughout the body, this work has important implications for the systemic effects of DNA damage-based anti-cancer therapies. Moreover, the detection of cisplatin adduct-containing DNA could be useful as a marker of cancer cell killing or side effects.
Page Count
75
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2024
Copyright
Copyright 2024, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0009-0004-9505-9415
