{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:42:42Z","timestamp":1789051362344,"version":"build-2803163510"},"reference-count":63,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Bialystok, Poland","award":["B.SUB.24.334"],"award-info":[{"award-number":["B.SUB.24.334"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cellular senescence plays a critical role in tumorigenesis and is recognized as a hallmark of colorectal cancer (CRC). Emerging evidence suggests that 5-fluorouracil (5-FU)-induced senescence may contribute to chemoresistance and tumor recurrence. Here, we investigated the effect of 5-FU on colon cancer cell senescence and whether MM-129 (pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine sulfonamide) can antagonize this activity. Senescence was identified by the expression of senescence-associated \u03b2-galactosidase (SA-\u03b2-gal) and cyclin-dependent kinase inhibitor 1A (p21) using qPCR, microscopy, flow cytometry, and immunohistochemistry. We also measured interleukin 6 (IL-6) and tumor necrosis factor (TNF-\u03b1) as key SASP cytokines, along with E-cadherin (CDH1), a marker of epithelial integrity. The SIRT1\/STAT3 pathway was evaluated to elucidate the mechanism of MM-129\u2032s action. MM-129 counteracted 5-FU-induced senescence in colon cancer models, reducing p21 levels in zebrafish xenografts and the number of SA-\u03b2-gal-positive cells in vitro and in tumor tissues from DLD-1 and HT-29 mouse xenografts. MM-129 also inhibited senescence-associated responses by suppressing SASP cytokines (IL-6, TNF-\u03b1) and restoring E-cadherin (CDH1), and it modulated the SIRT1\/STAT3 axis, which may underlie the observed senotherapeutic effects. In conclusion, MM-129 represents a novel senotherapeutic candidate. By modulating the SIRT1\/STAT3 axis, it may suppress the SASP and weaken pro-survival signaling, thereby facilitating selective clearance of senescent cells. Integrating senotherapeutics with conventional cancer therapies may enhance efficacy and open new avenues for translational research.<\/jats:p>","DOI":"10.3390\/cells14191498","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T07:46:49Z","timestamp":1758786409000},"page":"1498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["MM-129 Counteracts 5-Fluorouracil-Induced Cellular Senescence in Colon Cancer via SIRT1\/STAT3 Signaling Pathway"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0445-0993","authenticated-orcid":false,"given":"Hubert","family":"Klepacki","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Sieklucka","sequence":"additional","affiliation":[{"name":"Department of Monitored Pharmacotherapy, Medical University of Bialystok, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7452-8874","authenticated-orcid":false,"given":"Joanna","family":"Kalafut","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chod\u017aki 1, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5680-8859","authenticated-orcid":false,"given":"Krystyna","family":"Kowalczuk","sequence":"additional","affiliation":[{"name":"Department of Integrated Medical Care, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4475-873X","authenticated-orcid":false,"given":"Arkadiusz","family":"Surazynski","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9884-6068","authenticated-orcid":false,"given":"Mariusz","family":"Mojzych","sequence":"additional","affiliation":[{"name":"Faculty of Health Science, Collegium Medicum, The Mazovian Academy in Plock, Plac Dabrowskiego 2, 09-402 Plock, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2786-7179","authenticated-orcid":false,"given":"Anna","family":"Pryczynicz","sequence":"additional","affiliation":[{"name":"Department of General Pathomorphology, Medical University of Bialystok, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3751-0608","authenticated-orcid":false,"given":"Dariusz","family":"Pawlak","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-9853","authenticated-orcid":false,"given":"Natascia","family":"Tiso","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3985-4244","authenticated-orcid":false,"given":"Justyna","family":"Hermanowicz","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"},{"name":"Department of Clinical Pharmacy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/0014-4827(65)90211-9","article-title":"The limited in vitro lifetime of human diploid cell strains","volume":"37","author":"Hayflick","year":"1965","journal-title":"Exp. 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