{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:16:15Z","timestamp":1760145375607,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T00:00:00Z","timestamp":1721260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Veterans Affairs Office of Research &amp; Development","award":["#821-MR-37376"],"award-info":[{"award-number":["#821-MR-37376"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Current treatments for lymphoma are plagued by substantial toxicity and the inability to overcome drug resistance, leading to eventual relapse and rationalizing the development of novel, less toxic therapeutics and drug combinations. Histone deacetylase inhibitors (HDACis) are a broad class of epigenetic modulators that have been studied in multiple tumor types, including lymphoma. Currently, HDACis are FDA-approved for treating relapsed T-cell lymphomas and multiple myeloma, with ongoing trials in other lymphomas and solid tumors. As single agents, HDACis frequently elicit toxic side effects and have limited efficacy; therefore, many current treatment strategies focus on combinations to boost efficacy while attempting to minimize toxicity. Fermented wheat germ extract (FWGE) is a complementary agent that has shown efficacy in several malignancies, including lymphoma. Here, we utilize a more potent FWGE derivative, known as fermented wheat germ protein (FWGP), in combination with the HDACi AR42, to assess for enhanced activity. We report increased in vitro killing, cell cycle arrest, and in vivo efficacy for this combination compared to each agent alone with minimal toxicity, suggesting a potentially new, minimally toxic treatment modality for lymphoma.<\/jats:p>","DOI":"10.3390\/ijms25147866","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T10:39:26Z","timestamp":1721299166000},"page":"7866","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fermented Wheat Germ Protein with Histone Deacetylase Inhibitor AR42 Demonstrates Enhanced Cytotoxicity against Lymphoma Cells In Vitro and In Vivo"],"prefix":"10.3390","volume":"25","author":[{"given":"Joshua F.","family":"Meckler","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Levis","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanguo","family":"Kong","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert T.","family":"O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel P.","family":"Vang","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph M.","family":"Tuscano","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA"},{"name":"Department of Veterans Affairs, Northern California Healthcare System, Sacramento, CA 95652, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102443","DOI":"10.1016\/j.ctrv.2022.102443","article-title":"Treatment strategies for patients with diffuse large B-cell lymphoma","volume":"110","author":"Poletto","year":"2022","journal-title":"Cancer Treat. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e289","DOI":"10.1016\/S2352-3026(22)00033-3","article-title":"Treatment patterns and outcomes of patients with relapsed or refractory follicular lymphoma receiving three or more lines of systemic therapy (LEO CReWE): A multicentre cohort study","volume":"9","author":"Casulo","year":"2022","journal-title":"Lancet Haematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100826","DOI":"10.1016\/j.currproblcancer.2021.100826","article-title":"CAR T-cell therapy for B-cell lymphoma","volume":"46","author":"Denlinger","year":"2022","journal-title":"Curr. Probl. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Barisone, G.A., O\u2019donnell, R.T., Ma, Y., Abuhay, M.W., Lundeberg, K., Gowda, S., and Tuscano, J.M. (2018). A purified, fermented, extract of Triticum aestivum has lymphomacidal activity mediated via natural killer cell activation. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0190860"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1177\/153537020523000209","article-title":"Immunologic and Biochemical Effects of the Fermented Wheat Germ Extract Avemar","volume":"230","author":"Illmer","year":"2005","journal-title":"Exp. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12906-016-1138-5","article-title":"Antiproliferative and antimetabolic effects behind the anticancer property of fermented wheat germ extract","volume":"16","author":"Otto","year":"2016","journal-title":"BMC Complement. Altern. Med."},{"key":"ref_7","first-page":"787","article-title":"Avemar, a nontoxic fermented wheat germ extract, attenuates the growth of sensitive and 5-FdUrd\/Ara-C cross-resistant H9 human lymphoma cells through induction of apoptosis","volume":"21","author":"Saiko","year":"2009","journal-title":"Oncol. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/1475-2891-10-89","article-title":"Fermented wheat germ extract\u2014Nutritional supplement or anticancer drug?","volume":"10","author":"Mueller","year":"2011","journal-title":"Nutr. J."},{"key":"ref_9","first-page":"121725","article-title":"Fermented wheat germ extract induced cell death and enhanced cytotoxicity of cisplatin and 5-Fluorouracil on human hepatocellular carcinoma cells. Evidence-based complement","volume":"2013","author":"Tai","year":"2013","journal-title":"Altern. Med. Suppl."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"46408","DOI":"10.1074\/jbc.M206150200","article-title":"Fermented wheat germ extract inhibits glycolysis\/pentose cycle enzymes and induces apoptosis through poly(ADP-ribose) polymerase activation in Jurkat T-cell leukemia tumor cells","volume":"277","author":"Boros","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.canlet.2006.10.018","article-title":"Avemar, a nontoxic fermented wheat germ extract, induces apoptosis and inhibits ribonucleotide reductase in human HL-60 promyelocytic leukemia cells","volume":"250","author":"Saiko","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_12","first-page":"563","article-title":"Fermented wheat germ extract induces apoptosis and downregulation of major histocompatibility complex class I proteins in tumor T and B cell lines","volume":"20","author":"Hidvegi","year":"2002","journal-title":"Int. J. Oncol."},{"key":"ref_13","first-page":"570785","article-title":"Preclinical evaluation on the tumor suppression efficiency and combination drug effects of fermented wheat germ extract in human ovarian carcinoma cells","volume":"2015","author":"Wang","year":"2015","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7087","DOI":"10.3390\/cimb45090448","article-title":"A Fermented Wheat Germ Extract Contains Protein Components Active against NSCLC Xenografts In Vivo","volume":"45","author":"Levis","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/bs.acr.2018.02.006","article-title":"Advances and Challenges of HDAC Inhibitors in Cancer Therapeutics","volume":"138","author":"McClure","year":"2018","journal-title":"Adv. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/ijc.25660","article-title":"The novel histone deacetylase inhibitor, AR-42, inhibits gp130\/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells","volume":"129","author":"Zhang","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lucas, D.M., Alinari, L., West, D.A., Davis, M.E., Edwards, R.B., Johnson, A.J., Blum, K.A., Hofmeister, C.C., Freitas, M.A., and Parthun, M.R. (2010). The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-Cell malignancies In Vitro and In Vivo. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010941"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119504","DOI":"10.1016\/j.lfs.2021.119504","article-title":"Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy","volume":"277","author":"Ramaiah","year":"2021","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.bbrc.2015.05.078","article-title":"The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production","volume":"463","author":"Xu","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16367","DOI":"10.18632\/oncotarget.14829","article-title":"The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib\/dabrafenib-resistant melanoma cells in vitro and in vivo","volume":"8","author":"Booth","year":"2017","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.juro.2015.02.2918","article-title":"Synergy of Histone-Deacetylase Inhibitor AR-42 with Cisplatin in Bladder Cancer","volume":"194","author":"Li","year":"2015","journal-title":"J. Urol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1080\/10428194.2017.1298751","article-title":"A phase 1 trial of the HDAC inhibitor AR-42 in patients with multiple myeloma and T- and B-cell lymphomas","volume":"58","author":"Sborov","year":"2017","journal-title":"Leuk. Lymphoma"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1080\/10428194.2020.1719095","article-title":"Phase I study of AR-42 and decitabine in acute myeloid leukemia","volume":"61","author":"Liva","year":"2020","journal-title":"Leuk. Lymphoma"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1002\/lio2.643","article-title":"Early phase clinical studies of AR-42, a histone deacetylase inhibitor, for neurofibromatosis type 2-associated vestibular schwannomas and meningiomas","volume":"6","author":"Welling","year":"2021","journal-title":"Laryngoscope Investig. Otolaryngol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5155","DOI":"10.1038\/s41467-021-25332-w","article-title":"The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma","volume":"12","author":"Ny","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1200\/JCO.21.00944","article-title":"E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group","volume":"39","author":"Connolly","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31134","DOI":"10.18632\/oncotarget.5290","article-title":"HDAC inhibitor AR-42 decreases CD44 expression and sensitizes myeloma cells to lenalidomide","volume":"6","author":"Canella","year":"2015","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"824","DOI":"10.2119\/molmed.2015.00032","article-title":"Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma","volume":"21","author":"Kong","year":"2015","journal-title":"Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/j.leukres.2014.08.014","article-title":"Histone deacetylase inhibition enhances the lymphomacidal activity of the anti-CD22 monoclonal antibody HB22.7","volume":"38","author":"Kong","year":"2014","journal-title":"Leuk. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1158\/1535-7163.MCT-13-0963","article-title":"Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: A novel potential strategy in acute myelogenous leukemia","volume":"13","author":"Guzman","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1593\/neo.09204","article-title":"A rationally designed histone deacetylase inhibitor with distinct antitumor activity against ovarian cancer","volume":"11","author":"Yang","year":"2009","journal-title":"Neoplasia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"968","DOI":"10.3324\/haematol.2016.142406","article-title":"ENGAGE- 501: Phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma","volume":"101","author":"Batlevi","year":"2016","journal-title":"Haematologica"},{"key":"ref_33","first-page":"477","article-title":"Adjuvant fermented wheat germ extract (Avemar) nutraceutical improves survival of high-risk skin melanoma patients: A randomized, pilot, phase II clinical study with a 7-year follow-up","volume":"23","author":"Demidov","year":"2008","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1080\/01635581.2021.1952457","article-title":"Fermented Wheat Germ Extract (FWGE) as a Treatment Additive for Castration-Resistant Prostate Cancer: A Pilot Clinical Trial","volume":"74","author":"Weitzen","year":"2021","journal-title":"Nutr. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1080\/10915810701369709","article-title":"Safety studies regarding a standardized extract of fermented wheat germ","volume":"26","author":"Heimbach","year":"2007","journal-title":"Int. J. Toxicol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1196\/annals.1361.097","article-title":"Fermented wheat germ extract (Avemar) in the treatment of cancer and autoimmune diseases","volume":"1051","author":"Boros","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Barisone, G.A., Ngo, T., Tran, M., Cortes, D., Shahi, M.H., Nguyen, T.-V., Perez-Lanza, D., Matayasuwan, W., and D\u00edaz, E. (2012). Role of MXD3 in proliferation of DAOY human medulloblastoma cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038508"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7866\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:18:57Z","timestamp":1760109537000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7866"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,18]]},"references-count":37,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25147866"],"URL":"https:\/\/doi.org\/10.3390\/ijms25147866","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,7,18]]}}}