Ondrej Novotny
@img.cas.cz
IMG CAS
RESEARCH, TEACHING, or OTHER INTERESTS
Molecular Biology
Scopus Publications
Scopus Publications
Patrik Oleksak, David Rysanek, Marketa Vancurova, Pavla Vasicova, Alexandra Urbancokova, Josef Novak, Dominika Maurencova, Pavel Kashmel, Jana Houserova, Romana Mikyskova,et al.
American Chemical Society (ACS)
Romana Mikyskova, Olena Sapeg, Miroslav Psotka, Ondrej Novotny, Zdeněk Hodny, Sona Balintova, David Malinak, Jana Svobodova, Rudolf Andrys, David Rysanek,et al.
Spandidos Publications
Signal transducer and activator of transcription 3 (STAT3) signalling serves an important role in carcinogenesis and cellular senescence, and its inhibition in tumour cells represents an attractive therapeutic target. Premature cellular senescence, a process of permanent proliferative arrest of cells in response to various inducers, such as cytostatic drugs or ionizing radiation, is accompanied by morphological and secretory changes, and by altered susceptibility to chemotherapeutic agents, which can thereby complicate their eradication by cancer therapies. In the present study, the responsiveness of proliferating and docetaxel (DTX)-induced senescent cancer cells to small molecule STAT3 inhibitor Stattic and its analogues was evaluated using tumour cell lines. These agents displayed cytotoxic effects in cell viability assays on both proliferating and senescent murine TRAMP-C2 and TC-1 cells; however, senescent cells were markedly more resistant. Western blot analysis revealed that Stattic and its analogues effectively inhibited constitutive STAT3 phosphorylation in both proliferating and senescent cells. Furthermore, whether the Stattic-derived inhibitor K1836 could affect senescence induction or modulate the phenotype of senescent cells was evaluated. K1836 treatment demonstrated no effect on senescence induction by DTX. However, the K1836 compound significantly modulated secretion of certain cytokines (interleukin-6, growth-regulated oncogene α and monocyte chemoattractant protein-1). In summary, the present study demonstrated differences between proliferating and senescent tumour cells in terms of their susceptibility to STAT3 inhibitors and demonstrated the ability of the new STAT3 inhibitor K1836 to affect the secretion of essential components of the senescence-associated secretory phenotype. The present study may be useful for further development of STAT3 inhibitor-based therapy of cancer or age-related diseases.
Zofia Chrienova, David Rysanek, Patrik Oleksak, Dorota Stary, Marek Bajda, Milan Reinis, Romana Mikyskova, Ondrej Novotny, Rudolf Andrys, Adam Skarka,et al.
Frontiers Media SA
To date, the most studied drug in anti-aging research is the mTOR inhibitor – rapamycin. Despite its almost perfect anti-aging profile, rapamycin exerts one significant limitation – inappropriate physicochemical properties. Therefore, we have decided to utilize virtual high-throughput screening and fragment-based design in search of novel mTOR inhibiting scaffolds with suitable physicochemical parameters. Seven lead compounds were selected from the list of obtained hits that were commercially available (4, 5, and 7) or their synthesis was feasible (1, 2, 3, and 6) and evaluated in vitro and subsequently in vivo. Of all these substances, only compound 3 demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound 3 is a direct mTORC1 inhibitor. Last but not least, compound 3 was found to exhibit anti-SASP activity concurrently being relatively safe within the test of in vivo tolerability. All these outstanding results highlight compound 3 as a scaffold worthy of further investigation.