{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T03:04:47Z","timestamp":1773803087871,"version":"3.50.1"},"reference-count":25,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute\/National Institutes of Health","doi-asserted-by":"publisher","award":["#HHSN2612015000031"],"award-info":[{"award-number":["#HHSN2612015000031"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute\/National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA16059-20"],"award-info":[{"award-number":["P30 CA16059-20"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hematology Reports"],"abstract":"<jats:p>Interactions between the novel hypomethylating agent (HMA) thio-deoxycytidine (T-dCyd) and the BCL-2 antagonist ABT-199 (venetoclax) have been examined in human myelodysplastic syndrome (MDS) cells. The cells were exposed to agents alone or in combination, after which apoptosis was assessed, and a Western blot analysis was performed. Co-administration of T-dCyd and ABT-199 was associated with the down-regulation of DNA methyltransferase 1 (DNMT1) and synergistic interactions documented by a Median Dose Effect analysis in multiple MDS-derived lines (e.g., MOLM-13, SKM-1, and F-36P). Inducible BCL-2 knock-down significantly increased T-dCyd\u2019s lethality in MOLM-13 cells. Similar interactions were observed in the primary MDS cells, but not in the normal cord blood CD34+ cells. Enhanced killing by the T-dCyd\/ABT-199 regimen was associated with increased reactive oxygen species (ROS) generation and the down-regulation of the anti-oxidant proteins Nrf2 and HO-1, as well as BCL-2. Moreover, ROS scavengers (e.g., NAC) reduced lethality. Collectively, these data suggest that combining T-dCyd with ABT-199 kills MDS cells through an ROS-dependent mechanism, and we argue that this strategy warrants consideration in MDS therapy.<\/jats:p>","DOI":"10.3390\/hematolrep15010010","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T03:36:57Z","timestamp":1675395417000},"page":"91-100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Synergistic Interactions between the Hypomethylating Agent Thio-Deoxycytidine and Venetoclax in Myelodysplastic Syndrome Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Xiaoyan","family":"Hu","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jewel","family":"Nkwocha","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanika","family":"Sharma","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5457-7532","authenticated-orcid":false,"given":"Liang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Grant","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1002\/ajh.25950","article-title":"Myelodysplastic syndromes: 2021 update on diagnosis, risk stratification and management","volume":"95","author":"Chien","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/s41375-020-1003-x","article-title":"Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network","volume":"35","author":"Gu","year":"2021","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1080\/10428194.2020.1719098","article-title":"Venetoclax in acute myeloid leukemia\u2014Current and future directions","volume":"61","author":"Lachowiez","year":"2020","journal-title":"Leuk. Lymphoma"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1038\/s41591-018-0233-1","article-title":"Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia","volume":"24","author":"Pollyea","year":"2018","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14040","DOI":"10.1002\/jcp.28091","article-title":"The Bcl-2 inhibitor venetoclax inhibits Nrf2 antioxidant pathway activation induced by hypomethylating agents in AML","volume":"234","author":"Nguyen","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.1182\/bloodadvances.2020001482","article-title":"Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure","volume":"4","author":"Ball","year":"2020","journal-title":"Blood Adv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s00280-014-2503-z","article-title":"Novel DNA methyltransferase-1 (DNMT1) depleting anticancer nucleosides, 4\u2032-thio-2\u2032-deoxycytidine and 5-aza-4\u2032-thio-2\u2032-deoxycytidine","volume":"74","author":"Thottassery","year":"2014","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1124\/jpet.121.000758","article-title":"5-Aza-4\u2032-thio-2\u2032-deoxycytidine, a New Orally Bioavailable Nontoxic \u201cBest-in-Class\u201d: DNA Methyltransferase 1-Depleting Agent in Clinical Development","volume":"379","author":"Parker","year":"2021","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1158\/0008-5472.CAN-12-1365","article-title":"Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism","volume":"73","author":"Rahmani","year":"2013","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1158\/0008-5472.CAN-06-3964","article-title":"Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation","volume":"67","author":"Chen","year":"2007","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1053\/j.seminhematol.2014.05.008","article-title":"Targeting BCL2 for the treatment of lymphoid malignancies","volume":"51","author":"Anderson","year":"2014","journal-title":"Semin. Hematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzyme Regul."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1002\/gcc.22430","article-title":"Immunophenotypic, cytogenetic, and mutational characterization of cell lines derived from myelodysplastic syndrome patients after progression to acute myeloid leukemia","volume":"56","author":"Palau","year":"2017","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.bbamcr.2018.02.010","article-title":"Nrf2-Keap1 signaling in oxidative and reductive stress","volume":"1865","author":"Bellezza","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/2040620720955006","article-title":"Emerging treatment options for patients with high-risk myelodysplastic syndrome","volume":"11","author":"Bewersdorf","year":"2020","journal-title":"Ther Adv. Hematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s40164-019-0133-1","article-title":"Venetoclax with azacitidine targets refractory MDS but spares healthy hematopoiesis at tailored dose","volume":"8","author":"Jilg","year":"2019","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1038\/leu.2014.44","article-title":"BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies","volume":"28","author":"Bogenberger","year":"2014","journal-title":"Leukemia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1182\/blood-2018-08-868752","article-title":"Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia","volume":"133","author":"DiNardo","year":"2019","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1080\/16078454.2020.1843752","article-title":"The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis","volume":"25","author":"Liu","year":"2020","journal-title":"Hematology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1002\/j.1552-4604.1988.tb05730.x","article-title":"Comparative bioavailability of suprofen after coadministration with food or milk","volume":"28","author":"Chaikin","year":"1988","journal-title":"J. Clin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6653","DOI":"10.1158\/1078-0432.CCR-21-2139","article-title":"Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions","volume":"27","author":"Zavras","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrm2308","article-title":"The BCL-2 protein family: Opposing activities that mediate cell death","volume":"9","author":"Youle","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/bjc.2017.432","article-title":"Flavopiridol enhances ABT-199 sensitivity in unfavourable-risk multiple myeloma cells in vitro and in vivo","volume":"118","author":"Zhou","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.clml.2021.07.012","article-title":"SOHO State of the Art Updates and Next Questions: The Past, Present and Future of Venetoclax-Based Therapies in AML","volume":"21","author":"Inguva","year":"2021","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10833","DOI":"10.1073\/pnas.191208598","article-title":"The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species","volume":"98","author":"Ruefli","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Hematology Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2038-8330\/15\/1\/10\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:22:52Z","timestamp":1760120572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2038-8330\/15\/1\/10"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,2]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["hematolrep15010010"],"URL":"https:\/\/doi.org\/10.3390\/hematolrep15010010","relation":{},"ISSN":["2038-8330"],"issn-type":[{"value":"2038-8330","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,2]]}}}