{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T13:10:56Z","timestamp":1785244256622,"version":"3.55.0"},"reference-count":61,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Arizona Cancer Center","award":["P30CA023074"],"award-info":[{"award-number":["P30CA023074"]}]},{"name":"Courtney\u2019s Courage","award":["P30CA023074"],"award-info":[{"award-number":["P30CA023074"]}]},{"name":"PANDA","award":["P30CA023074"],"award-info":[{"award-number":["P30CA023074"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Bendamustine (BEN) combined with rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed\/refractory (R\/R) MCL. We recently reported that a novel oral formulation of BEN exhibits comparable efficacy to the intravenous counterpart. In this study, we investigated the efficacy of oral BEN administered alone or in combination with the oral BCL-2 inhibitor Venetoclax (VEN) and\/or the oral BTKi Acalabrutinib (ACAL), against two human MCL cell lines (Jeko-1 and Z-138) representative of the R\/R disease subtype. Methods: We performed in vitro analyses using MTS viability and Annexin V\/PI apoptosis assays. For the in vivo studies, all treatments were administered via oral gavage in xenograft mouse models. Therapeutic efficacy was evaluated by monitoring tumor growth and survival. Results: BEN induced significant cytotoxicity in both cell lines at low, clinically relevant concentrations. In contrast, VEN demonstrated limited efficacy as monotherapy, with Z-138 showing sensitivity only at high doses. However, combining BEN with VEN with or without ACAL, enhanced apoptosis and cytotoxicity, with more pronounced effects in Z-138. In vivo, oral BEN significantly reduced tumor growth and prolonged survival in both xenograft models. In the Z-138 model, the addition of VEN \u00b1 ACAL further improved survival outcomes. Conclusions: Our findings support the efficacy of oral BEN as both a monotherapy and as part of an all-oral treatment regimen for MCL. These results warrant further investigation into the clinical potential of oral BEN, particularly in combination with targeted agents.<\/jats:p>","DOI":"10.3390\/cancers17111889","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T03:58:52Z","timestamp":1749095932000},"page":"1889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Triple Oral Combination of Bendamustine, Acalabrutinib, and Venetoclax Demonstrates Efficacy Against Mantle Cell Lymphoma In Vitro and In Vivo"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5469-6889","authenticated-orcid":false,"given":"Dimitrios","family":"Filioglou","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Santa-Cruz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geovana S. F.","family":"Leite","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan W.","family":"Davini","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan J.","family":"Cracchiolo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5338-7905","authenticated-orcid":false,"given":"Forrest L.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"},{"name":"School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ 85721, USA"},{"name":"University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Husnain","sequence":"additional","affiliation":[{"name":"University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Medicine, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"},{"name":"School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ 85721, USA"},{"name":"University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasilios","family":"Voudouris","sequence":"additional","affiliation":[{"name":"Exinda Therapeutics LLC, El Dorado Hills, CA 95762, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-6965","authenticated-orcid":false,"given":"Emmanuel","family":"Katsanis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"},{"name":"University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Medicine, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/hon.3149","article-title":"Mantle cell lymphoma-Update on molecular biology, prognostication and treatment approaches","volume":"41","author":"Silkenstedt","year":"2023","journal-title":"Hematol. 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