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Use of cucurbitacin D for cancer treatment
Malátová, Iva ; Šírová, Milada (advisor) ; Dibus, Michal (referee)
Cucurbitacins are highly oxidized triterpenoids commonly found in plants, especially in the family Cucurbitaceae. There are seventeen types of cucurbitacins and each of them has its derivatives. Cucurbitacins with the most prominent antitumor activity are B, D, E and I. Of these, cucurbitacin B and D are the most common in plants. This work focuses mainly on cucurbitacin D. Cucurbitacin D often induces apoptosis in tumor cells, cell cycle arrest and thereby stops cell proliferation. Indicators of these processes are reduced levels of Bcl-xL, Bcl-2, p21, p27 and cyclins A and B proteins. The main effect of cucurbitacin D on tumor cells is the inhibition of the STAT3 signaling pathway. Whether this pathway is affected at the level of phosphorylation, dimerization, or STAT3 translocation into the nukleus, the result is blocking transcription of genes, which are activated thanks to STAT3 pathway. These are primarily genes that affect tumor growth, angiogenesis, cell invasion, and immune escape. Cucurbitacin D also affects other cell components and processes, such as the NF-κB transcription factor, the enzyme complex of proteasome and inflammasome. However, current knowledge of cucurbitacin D and its mechanism of action is not yet sufficient for its use as an antitumor drug, although the results of its testing...
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Immune response and tumor microenvironment in the treatment with polymer cytotoxic drugs
Malátová, Iva ; Šírová, Milada (advisor) ; Stollinová Šromová, Lucie (referee)
Chemotherapy is still one of the most widely used anticancer therapies. It is mostly about inhibiting the proliferation of rapidly dividing cells, so it is not selective for tumor cells. As a result, many undesirable side effects are associated with chemotherapy. The disadvantageous properties of chemotherapeutics can be largely eliminated by using conjugates of polymers with low molecular weight drugs. An example of such a conjugate is a doxorubicin-linked HPMA polymer. In addition to the properties obtained by polymer binding, such as achieving solubility in aqueous solutions, reducing systemic toxicity, increasing the maximum tolerated dose, or passive targeting by the EPR effect, the fact that doxorubicin induces immunogenic cell death is used in therapy with this drug. It has already been shown that after complete cure of the experimental mice with polymeric conjugates of HPMA with doxorubicin, some mice develop long-term resistance to re-inoculation with a lethal dose of tumor cells. Resistance is specific to the particular line of tumor cells from which the mouse was cured, and CD8+ cytotoxic T cells and IFNγ play an important role. In this work, we monitored changes in the proportion of immune populations and their activation markers after treatment with HPMA-based polymers with doxorubicin...
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Use of cucurbitacin D for cancer treatment
Malátová, Iva ; Šírová, Milada (advisor) ; Dibus, Michal (referee)
Cucurbitacins are highly oxidized triterpenoids commonly found in plants, especially in the family Cucurbitaceae. There are seventeen types of cucurbitacins and each of them has its derivatives. Cucurbitacins with the most prominent antitumor activity are B, D, E and I. Of these, cucurbitacin B and D are the most common in plants. This work focuses mainly on cucurbitacin D. Cucurbitacin D often induces apoptosis in tumor cells, cell cycle arrest and thereby stops cell proliferation. Indicators of these processes are reduced levels of Bcl-xL, Bcl-2, p21, p27 and cyclins A and B proteins. The main effect of cucurbitacin D on tumor cells is the inhibition of the STAT3 signaling pathway. Whether this pathway is affected at the level of phosphorylation, dimerization, or STAT3 translocation into the nukleus, the result is blocking transcription of genes, which are activated thanks to STAT3 pathway. These are primarily genes that affect tumor growth, angiogenesis, cell invasion, and immune escape. Cucurbitacin D also affects other cell components and processes, such as the NF-κB transcription factor, the enzyme complex of proteasome and inflammasome. However, current knowledge of cucurbitacin D and its mechanism of action is not yet sufficient for its use as an antitumor drug, although the results of its testing...
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