{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:42:59Z","timestamp":1784162579270,"version":"3.55.0"},"reference-count":55,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Long-term, curative treatment of cutaneous T-cell lymphomas (CTCL) remains a major challenge. Therapy resistance is often based on apoptosis deficiency, and may depend on antiapoptotic Bcl-2 proteins, such as Bcl-2, Bcl-xL, Bcl-w and Mcl-1. For their targeting, several antagonists have been generated, which mimic the Bcl-2 homology domain 3 (BH3 mimetics). As dysregulation and overexpression of Mcl-1 has been reported in CTCL, the use of Mcl-1 inhibitors appears as an attractive strategy. Here, we investigated the effects of the selective Mcl-1 inhibitor S63845 in a series of four CTCL cell lines, in comparison to ABT-263 and ABT-737 (inhibitors of Bcl-2, Bcl-xL and Bcl-w). In two cell lines (HH, HuT-78), S63845 resulted in significant apoptosis induction, decrease in cell viability, loss of mitochondrial membrane potential and caspase activation, while two other cell lines (MyLa, SeAx) remained completely resistant. An inverse correlation was found, as S63845-resistant cells were highly sensitive to ABT-263\/-737, and S63845-sensitive cells showed only moderate sensitivity to ABTs. Combinations of S63845 and ABT-263 partially yielded synergistic effects. As concerning Bcl-2 protein expression, weaker Mcl-1 expression was found in S63845-resistant MyLa and SeAx, while for Bcl-2 and Bcl-xL, the lowest expression was found in the highly sensitive cell line HH. The most striking difference between S63845-resistant and -sensitive cells was identified for Bcl-w, which was exclusively expressed in S63845-resistant cells. Thus, CTCL may be efficiently targeted by BH3 mimetics, providing the right target is preselected, and Bcl-w expression may serve as a suitable marker.<\/jats:p>","DOI":"10.3390\/ijms232012471","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T21:18:02Z","timestamp":1666127882000},"page":"12471","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sensitivity of Cutaneous T-Cell Lymphoma Cells to the Mcl-1 Inhibitor S63845 Correlates with the Lack of Bcl-w Expression"],"prefix":"10.3390","volume":"23","author":[{"given":"Uly","family":"Sumarni","sequence":"first","affiliation":[{"name":"Department of Dermatology, Venerology und Allergology, Skin Cancer Center, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venerology und Allergology, Skin Cancer Center, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3922-3327","authenticated-orcid":false,"given":"Tobias","family":"Sinnberg","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venerology und Allergology, Skin Cancer Center, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8533-1519","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Eberle","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venerology und Allergology, Skin Cancer Center, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/bjd.20895","article-title":"Transcriptomic changes during stage progression of mycosis fungoides: From translational analyses to their potential clinical implications","volume":"186","author":"Dobos","year":"2022","journal-title":"Br. J. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1182\/blood-2018-11-881268","article-title":"The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas","volume":"133","author":"Willemze","year":"2019","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4730","DOI":"10.1200\/JCO.2009.27.7665","article-title":"Survival outcomes and prognostic factors in mycosis fungoides\/S\u00e9zary syndrome: Validation of the revised International Society for Cutaneous Lymphomas\/European Organisation for Research and Treatment of Cancer staging proposal","volume":"28","author":"Agar","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41572-021-00296-9","article-title":"Cutaneous T cell lymphoma","volume":"7","author":"Dummer","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Eberle, J. (2019). Countering TRAIL Resistance in Melanoma. Cancers, 11.","DOI":"10.3390\/cancers11050656"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/j.1396-0296.2003.01642.x","article-title":"Phototherapy for cutaneous T-cell lymphoma","volume":"16","author":"Baron","year":"2003","journal-title":"Dermatol. Ther."},{"key":"ref_8","first-page":"1234","article-title":"Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: Relevance to mechanism of therapeutic action","volume":"8","author":"Zhang","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1038\/jid.2012.125","article-title":"Apoptosis induction by SAHA in cutaneous T-cell lymphoma cells is related to downregulation of c-FLIP and enhanced TRAIL signaling","volume":"132","author":"Fecker","year":"2012","journal-title":"J. Invest. Derm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jdermsci.2006.05.004","article-title":"Extracorporeal photopheresis: A focus on apoptosis and cytokines","volume":"43","author":"Bladon","year":"2006","journal-title":"J. Derm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/nri2115","article-title":"Life and death in peripheral T cells","volume":"7","author":"Krammer","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"409","DOI":"10.2174\/138920208785699571","article-title":"Expression and function of bcl-2 proteins in melanoma","volume":"9","author":"Eberle","year":"2008","journal-title":"Curr. Genom."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/nrm2952","article-title":"Mitochondria and cell death: Outer membrane permeabilization and beyond","volume":"11","author":"Tait","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of apoptosis signalling pathways by reactive oxygen species","volume":"1863","year":"2016","journal-title":"Biochim. Et Biophys. Acta BBA Mol. Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/sj.cdd.4401160","article-title":"Many cuts to ruin: A comprehensive update of caspase substrates","volume":"10","author":"Fischer","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/cdd.2013.139","article-title":"Building blocks of the apoptotic pore: How Bax and Bak are activated and oligomerize during apoptosis","volume":"21","author":"Westphal","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/nature08822","article-title":"The landscape of somatic copy-number alteration across human cancers","volume":"463","author":"Beroukhim","year":"2010","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"418","DOI":"10.3390\/cells3020418","article-title":"Mcl-1 ubiquitination: Unique regulation of an essential survival protein","volume":"3","author":"Mojsa","year":"2014","journal-title":"Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1038\/leu.2012.367","article-title":"MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma","volume":"27","author":"Wenzel","year":"2013","journal-title":"Leukemia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1517\/13543784.2011.609167","article-title":"Targeting Mcl-1 for the therapy of cancer","volume":"20","author":"Quinn","year":"2011","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1186\/s13046-021-02157-5","article-title":"BH3-mimetics: Recent developments in cancer therapy","volume":"40","author":"Townsend","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3421","DOI":"10.1158\/0008-5472.CAN-07-5836","article-title":"ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor","volume":"68","author":"Tse","year":"2008","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nature03579","article-title":"An inhibitor of Bcl-2 family proteins induces regression of solid tumours","volume":"435","author":"Oltersdorf","year":"2005","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature19830","article-title":"The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models","volume":"538","author":"Kotschy","year":"2016","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/s41418-019-0486-3","article-title":"Saga of Mcl-1: Regulation from transcription to degradation","volume":"27","author":"Senichkin","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1038\/leu.2016.49","article-title":"Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance","volume":"30","author":"Spinner","year":"2016","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1182\/blood-2018-07-865527","article-title":"Biomarker-driven strategy for MCL1 inhibition in T-cell lymphomas","volume":"133","author":"Koch","year":"2019","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/path.1341","article-title":"Expression of apoptosis regulators in cutaneous T-cell lymphoma (CTCL) cells","volume":"200","author":"Zhang","year":"2003","journal-title":"J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e839","DOI":"10.1038\/cddis.2013.344","article-title":"ROS-dependent phosphorylation of Bax by wortmannin sensitizes melanoma cells for TRAIL-induced apoptosis","volume":"4","author":"Quast","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"W739-43","DOI":"10.1093\/nar\/gkac382","article-title":"SynergyFinder 3.0: An interactive analysis and consensus interpretation of multi-drug synergies across multiple samples","volume":"50","author":"Ianevski","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1182\/blood-2016-03-704908","article-title":"Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: Pivotal role of MCL1","volume":"128","author":"Gong","year":"2016","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1038\/s41388-019-1122-x","article-title":"Potent efficacy of MCL-1 inhibitor-based therapies in preclinical models of mantle cell lymphoma","volume":"39","author":"Dengler","year":"2020","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1158\/1535-7163.MCT-21-0511","article-title":"Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas","volume":"21","author":"Klanova","year":"2022","journal-title":"Mol. Cancer Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3263","DOI":"10.1038\/s41467-018-05506-9","article-title":"Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma","volume":"9","author":"Manzano","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/s41419-019-2156-2","article-title":"Side-by-side comparison of BH3-mimetics identifies MCL-1 as a key therapeutic target in AML","volume":"10","author":"Ewald","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/jid.2011.316","article-title":"Nonsteroidal anti-inflammatory drugs induce apoptosis in cutaneous T-cell lymphoma cells and enhance their sensitivity for TNF-related apoptosis-inducing ligand","volume":"132","author":"Braun","year":"2012","journal-title":"J. Invest. Derm."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sumarni, U., Reidel, U., and Eberle, J. (2021). Targeting Cutaneous T-Cell Lymphoma Cells by Ingenol Mebutate (PEP005) Correlates with PKC\u03b4 Activation, ROS Induction as Well as Downregulation of XIAP and c-FLIP. Cells, 10.","DOI":"10.3390\/cells10050987"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.3324\/haematol.2019.220525","article-title":"Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma","volume":"105","author":"Smith","year":"2020","journal-title":"Haematologica"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Valiulien\u0117, G., Vitkevi\u010dien\u0117, A., Skliut\u0117, G., Borutinskait\u0117, V., and Navakauskien\u0117, R. (2021). Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling. Molecules, 26.","DOI":"10.3390\/molecules26082303"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1182\/blood-2007-12-130781","article-title":"The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies","volume":"112","author":"Paoluzzi","year":"2008","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1182\/blood-2007-06-098012","article-title":"BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia","volume":"111","author":"Schlis","year":"2008","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5973","DOI":"10.1158\/1078-0432.CCR-11-0955","article-title":"ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high\/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents","volume":"17","author":"Touzeau","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.1182\/blood-2010-11-317438","article-title":"ABT-737 is highly effective against molecular subgroups of multiple myeloma","volume":"118","author":"Bodet","year":"2011","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1172\/JCI89486","article-title":"BCL-W has a fundamental role in B cell survival and lymphomagenesis","volume":"127","author":"Adams","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1182\/bloodadvances.2019000541","article-title":"BCL-W is dispensable for the sustained survival of select Burkitt lymphoma and diffuse large B-cell lymphoma cell lines","volume":"4","author":"Diepstraten","year":"2020","journal-title":"Blood Adv."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13045-021-01079-1","article-title":"Targeting MCL-1 in cancer: Current status and perspectives","volume":"14","author":"Wang","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1080\/10428194.2020.1845332","article-title":"Safety and efficacy of navitoclax, a BCL-2 and BCL-X(L) inhibitor, in patients with relapsed or refractory lymphoid malignancies: Results from a phase 2a study","volume":"62","author":"Leonard","year":"2021","journal-title":"Leuk Lymphoma"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1158\/2159-8290.CD-20-1465","article-title":"Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma","volume":"11","author":"Pullarkat","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_49","unstructured":"Prelude, T. (2022, June 01). A Study of PRT1419 Injection in Patients With Relapsed\/Refractory Hematologic Malignancies, Available online: https:\/\/ClinicalTrials.gov\/show\/NCT04543305."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6913","DOI":"10.1021\/acs.jmedchem.9b00134","article-title":"Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity","volume":"62","author":"Ondi","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/BF02631086","article-title":"Establishment of two continuous T-cell strains from a single plaque of a patient with mycosis fungoides","volume":"28","author":"Kaltoft","year":"1992","journal-title":"Vitr. Cell Dev. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/BF00431220","article-title":"A continuous T-cell line from a patient with S\u00e9zary syndrome","volume":"279","author":"Kaltoft","year":"1987","journal-title":"Arch. Derm. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1182\/blood.V55.3.409.409","article-title":"Mitogen Requirements for the In Vitro Propagation of Cutaneous T-Cell Lymphomas","volume":"55","author":"Gazdar","year":"1980","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/ijc.2910490218","article-title":"Establishment of an IL-2 independent, human T-cell line possessing only the p70 IL-2 receptor","volume":"49","author":"Starkebaum","year":"1991","journal-title":"Int J. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"9131","DOI":"10.1038\/sj.onc.1207228","article-title":"CD95\/Fas signaling in human melanoma cells: Conditional expression of CD95L\/FasL overcomes the intrinsic apoptosis resistance of malignant melanoma and inhibits growth and progression of human melanoma xenotransplants","volume":"22","author":"Eberle","year":"2003","journal-title":"Oncogene"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12471\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:56:30Z","timestamp":1760144190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12471"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,18]]},"references-count":55,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms232012471"],"URL":"https:\/\/doi.org\/10.3390\/ijms232012471","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,18]]}}}