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- Ek, Frida,1993-Uppsala universitet,Cancerfarmakologi och beräkningsmedicin (author)
Quiescent cancer cells : Three-dimensional cell models for evaluation of new therapeutics
- BookEnglish2022
Publisher, publication year, extent ...
- Uppsala :Uppsala universitet,2022
- 58 s.
- electronicrdacarrier
Numbers
- LIBRIS-ID:oai:DiVA.org:uu-483620
- https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-483620URI
Supplementary language notes
- Language:English
- Summary in:English
Part of subdatabase
- SwePubSwePub
Classification
Varying forms of title
- Vilande cancerceller :Tredimensionella cellmodeller för utvärdering av nya cancerläkemedel
Notes
- Inadequate metabolic conditions in solid tumors lead to the formation of quiescent cancer cells that are suspended in a transient cell cycle arrest. When conditions change, quiescent cancer cells can re-enter the cell cycle and cause recurrence. Drug screening efforts have revealed mitochondrial oxidative phosphorylation as a unique metabolic dependency in quiescent cancer cells. The anthelmintic drug nitazoxanide is an inhibitor of oxidative phosphorylation and preferentially active against quiescent cancer cells in multicellular tumor spheroids. In this thesis, we employed current and developed new models of quiescent cancer cells and applied live cell imaging for improved preclinical evaluation of cancer drugs in hepatocellular and colorectal carcinoma cell lines. As part of this work, a new assay to measure mitochondrial membrane potential in three-dimensional cell models was developed, an application of the JC-1 assay, and we demonstrated that the preferential activity against quiescent cancer cells of nitazoxanide is shared by two kinase inhibitors: sorafenib and regorafenib. The sensitivity of quiescent cancer cells to nitazoxanide, sorafenib, and regorafenib correlated with the disruption of the mitochondrial membrane potential. Nitazoxanide and sorafenib, in combination, caused an additive decrease in viability, mitochondrial membrane potential, and colony regrowth capacity. Furthermore, we developed a quiescent hollow fiber assay and implemented an improved analysis using live cell imaging and adenosine triphosphate analysis. Hypoxia and cancer cell quiescence were enriched in hollow fiber macrocapsules over time, and the culture conditions affected nitazoxanide sensitivity. Additionally, we used basement membrane extract gel to support cell growth in hollow fiber macrocapsules and implanted macrocapsules in mice. We observed that the in vivo environment was favorable to cell growth. Through this characterization of the quiescent hollow fiber assay, we were able to outline important paths for future research.
Subject headings and genre
- MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
- MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
- Cancer
- cancer cell quiescence
- dormancy
- three-dimensional
- multicellular tumor spheroids
- model development
- cancer pharmacology
- mitochondria
- OXPHOS
- colorectal carcinoma
- hepatocellular carcinoma
- Medicinsk vetenskap
- Medical Science
Added entries (persons, corporate bodies, meetings, titles ...)
- Fryknäs, MårtenUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)mafry516 (thesis advisor)
- Jarvius, MalinUppsala universitet,Cancerfarmakologi och beräkningsmedicin,Science for Life Laboratory, SciLifeLab(Swepub:uu)maemi734 (thesis advisor)
- Larsson, RolfUppsala universitet,Cancerfarmakologi och beräkningsmedicin,Klinisk immunologi(Swepub:uu)rolflars (thesis advisor)
- Uppsala universitetCancerfarmakologi och beräkningsmedicin (creator_code:org_t)
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- Ek, Frida, 1993-
- Fryknäs, Mårten
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- Larsson, Rolf
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- MEDICAL AND HEALTH SCIENCES
- MEDICAL AND HEAL ...
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- Uppsala University
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