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Registration Number

0225U003730, (0124U003513) , R & D reports

Title

Dual targeting of tumor-specific vulnerabilities by novel thiosemicarbazone derivatives

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Дослідження низхідних сигнальних шляхів р53 та індукції ЕР стресу за дії тіосемікарбазонів COTI-2, COTI-NMe2 та KP1550 у злоякісних клітинах з різним функціональним станом ТР53

Head

Stojka Rostyslav S., д.б.н.

Registration Date

09-08-2025

Organization

Institute of Cell Biology of the National Academy of Sciences of Ukraine

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The project is aimed at the development of novel effective approaches for cancer treatment by targeting two main tumor-specific vulnerabilities - abnormally high expression of mutant p53 protein and immunological tolerance to cancer. In order to reach these goals, novel thiosemicarbazone derivatives - COTI-2, COTI-NMe2 and KP1550, which are characterized by a unique dual action towards malignant cells, will be addressed here.

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 Time-dependent changes in expression of proteins involved in ER stress and apoptosis in colon cancer cells with different TP53 status under the action of novel α-N-heterocyclic thiocarbazone derivatives were investigated. It was demonstrated that basic mechanism of action of these compounds is endoplasmic reticulum stress, manifested by the early activation of the phosphorylated form of ERK 1/2 kinase already at 6 hours and the transcription factor eIF2a at 12 hours. This process was accompanied by a sharp increase in the expression of the cell cycle regulator protein p21Waf1/Cip1 already at the 6h timepoint, indicating cell growth arrest in the G1 phase of the cell cycle. We did not detect any changes in the expression of the Bax protein, while a slight cleavage of the PARP-1 protein was observed only at 24 hours of exposure to the studied substances. All this indicates a weak induction of apoptosis by low doses of thiosemicarbazones in tumor cells. Fluorescence microscopy revealed massive vacuolization of the cytosol of target cells under the action of these compounds, which is a typical sign of another form of cell death – paraptosis. This process occurred regardless of the TP53 status in the studied cell lines. A further increase in the concentrations of thiocarbazones from 10 to 25 μM significantly changed their mode of action. We observed a sharp time-dependent increase in p53 protein level, which was particularly pronounced in tumor cells with TP53 mutations. This phenomenon was accompanied by a decrease in the expression of the direct target of p53 – the p21Waf1/Cip1 protein, and the early appearance of the cleaved form of the PARP-1 protein as early as the 6h in cells with TP53 mutations, which is a typical sign of the transition of the cell from cell cycle arrest to apoptosis. This indicates a “switch” between ER stress and apoptosis under the action of high doses of the studied thiocarbazones due to functional reactivation of mutant form of p53 protein.

Product Description

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Panchuk Rostyslav R.
Skorokhid Nadiia R.

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2025-08-09