{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:04:19Z","timestamp":1784005459551,"version":"3.55.0"},"reference-count":24,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T00:00:00Z","timestamp":1783814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: The search for new drugs which could suppress drug resistance development in tumor cells is extremely important for clinical practice. Inhibitors of cell signaling pathways that control cell proliferation and death can be used in complex therapy of malignant tumors. Methods: Cell cycle assay using flow cytometry, In Vitro Cell Viability Assay Cell chemosensitivity was analyzed by direct cell counting after trypan blue staining using a microscope. Results: In the present work, we have shown that the combined action of doxorubicin and XMU-MP-1, the MST1\/2 kinase inhibitor in the Hippo signaling pathway, prevents drug resistance development in Namalwa cells, significantly slows drug resistance development in K562 cells, and restores the sensitivity of resistant K562 cells to doxorubicin. We have shown that compared to monotherapy, the combination of doxorubicin and XMU-MP-1 causes a significant decrease in cell division rate and cell death in hematological tumor cells such as Burkitt\u2019s lymphoma Namalwa and chronic myeloid leukemia (CML) K562 cells. Cell cycle analysis revealed that the combined action of XMU-MP-1 and doxorubicin caused a catastrophic cell cycle disruption and a significant increase in the number of cells undergoing apoptosis containing fragmented DNA. Conclusions: XMU-MP-1 can be potentially used in combination with anthracyclines for the treatment of hematological malignancies and, in particular, drug-resistant cancer types.<\/jats:p>","DOI":"10.3390\/ph19071075","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T07:28:27Z","timestamp":1783927707000},"page":"1075","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["XMU-MP-1, the Hippo Signaling Pathway MST-1 Kinase Inhibitor, Prevents the Development of Drug Resistance to Doxorubicin in Hematological Tumor Cells"],"prefix":"10.3390","volume":"19","author":[{"given":"Alexander G.","family":"Stepchenko","sequence":"first","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3744-2262","authenticated-orcid":false,"given":"Elizaveta V.","family":"Pankratova","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow 119334, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.5483\/BMBRep.2023-0094","article-title":"Emerging role of Hippo pathway in the regulation of hematopoiesis","volume":"56","author":"Kim","year":"2023","journal-title":"BMB Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109927","DOI":"10.1016\/j.isci.2024.109927","article-title":"YAP condensates are highly organized hubs","volume":"27","author":"Hao","year":"2024","journal-title":"iScience"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.ccell.2016.05.005","article-title":"YAP\/TAZ at the Roots of Cancer","volume":"29","author":"Zanconato","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1146\/annurev-biochem-013118-111829","article-title":"The Hippo Pathway: Biology and Pathophysiology","volume":"88","author":"Ma","year":"2019","journal-title":"Annu. Rev. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"676","DOI":"10.2174\/1389201023666220617150346","article-title":"Dysregulated YAP1\/Hippo Pathway Contributes to Doxorubicin (ADM) Resistance in Acute Myeloid Leukemia (AML)","volume":"24","author":"Song","year":"2023","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_6","unstructured":"Augeri, D.J., Bagdanoff, J.T., Baugh, S.D.P., Carlsen, M., Carson, K.G., Gilleran, J.A., He, W., Oravecz, T., Salojin, K., and Sung, L. (2013). MST1 Kinase Inhibitors and Method of Use Thereof. (Patent CN103429582A)."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"352ra108","DOI":"10.1126\/scitranslmed.aaf2304","article-title":"Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration","volume":"8","author":"Fan","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_8","unstructured":"Liu, Q.S., Liu, J., Wu, Y., Wang, W.L., Wang, B.L., Qi, Z.P., Wang, J.J., Wang, W.C., Qi, S., and Wang, L. (2022). MST1 Kinase Inhibitors and Their Use. (Patent JP2022504601A)."},{"key":"ref_9","unstructured":"Liu, Q.S., Liu, J., Wu, Y., Wang, W.L., Wang, B.L., Qi, Z.P., Wang, J.J., Wang, W.C., Qi, S., and Wang, L. (2021). Mst1 Kinase Inhibitor and Use Thereof. (Patent EP3868762A1)."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3956","DOI":"10.1111\/bph.14795","article-title":"Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU-MP-1, protects the heart against adverse effects during pressure overload","volume":"176","author":"Triastuti","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Cheng, J., Jing, Y., Kang, D., Yang, L., Li, J., Yu, Z., Peng, Z., Li, X., Wei, Y., and Gong, Q. (2018). The Role of Mst1 in Lymphocyte Homeostasis and Function. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00149"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1111\/jcmm.17203","article-title":"MST1\/2 inhibitor XMU-MP-1 alleviates the injury induced by ionizing radiation in haematopoietic and intestinal system","volume":"26","author":"Zhou","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_13","unstructured":"Wu, D.P., Hu, S.H., Liu, Y.F., Lei, L., An, J.N., Wang, X.Q., Liu, T.H., and Xu, Y. (2022). Application of XMU-MP-1 in Preparation of Medicine for Preventing and\/or Treating Immune Thrombocytopenia ITP, China. (Patent CN114366750B)."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Stepchenko, A.G., Georgieva, S.G., and Pankratova, E.V. (2025). XMU-MP-1, Inhibitor of STE20-like MST1\/2 Kinases of the Hippo Signaling Pathway, Suppresses the Cell Cycle, Activates Apoptosis and Autophagy, and Induces Death of Hematopoietic Tumor Cells. Pharmaceuticals, 18.","DOI":"10.20944\/preprints202502.0217.v2"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/0145-2126(90)90009-X","article-title":"Mechanisms involved in the development of adriamycin resistance in human leukemic cells","volume":"14","author":"Kato","year":"1990","journal-title":"Leuk. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lazarovski, A. (2019). ABC-transporters and drug efflux in hematologic cancers. Drug Efflux Pumps in Cancer Resistance Pathways: From Molecular Recognition and Characterization to Possible Inhibition Strategies in Chemotherapy, Academic Press.","DOI":"10.1016\/B978-0-12-816434-1.00006-1"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Catalano, A., Iacopetta, D., Ceramella, J., Scumaci, D., Giuzio, F., Saturnino, C., Aquaro, S., Rosano, C., and Sinicropi, M.S. (2022). Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies. Molecules, 27.","DOI":"10.3390\/molecules27030616"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e70246","DOI":"10.1002\/ctm2.70246","article-title":"SH3GL1-activated FTH1 inhibits ferroptosis and confers doxorubicin resistance in diffuse large B-cell lymphoma","volume":"15","author":"Duan","year":"2025","journal-title":"Clin. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.bbrc.2017.05.031","article-title":"STAT3 mediates multidrug resistance of Burkitt lymphoma cells by promoting antioxidant feedback","volume":"488","author":"Zeng","year":"2017","journal-title":"Biochem Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"621","DOI":"10.2174\/138920111795164075","article-title":"Regulation of ABC transporter function via phosphorylation by protein kinases","volume":"12","author":"Stolarczyk","year":"2011","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Egorshina, A.Y., Zamaraev, A.V., Kaminskyy, V.O., Radygina, T.V., Zhivotovsky, B., and Kopeina, G.S. (2022). Necroptosis as a Novel Facet of Mitotic Catastrophe. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073733"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nm.3562","article-title":"Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers","volume":"20","author":"Cottini","year":"2014","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13008-020-00067-0","article-title":"XMU-MP-1 induces growth arrest in a model of human mini-organ and antagonises cell cycle-dependent paclitaxel cytotoxicity","volume":"15","author":"Mitchell","year":"2020","journal-title":"Cell Div."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1134\/S0012496624600635","article-title":"Inhibition of MST1\/2 Kinases of the Hippo Signaling Pathway Enhances Antitumor Chemotherapy in Hematological Cancers","volume":"520","author":"Stepchenko","year":"2025","journal-title":"Dokl. Biol. Sci."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1075\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T04:17:13Z","timestamp":1784002633000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,12]]},"references-count":24,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ph19071075"],"URL":"https:\/\/doi.org\/10.3390\/ph19071075","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,12]]}}}