{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:06:26Z","timestamp":1788926786341,"version":"build-2803163510"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/501100004621","name":"Kerman University of Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004621","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Med Oncol"],"DOI":"10.1007\/s12032-026-03353-z","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T06:48:36Z","timestamp":1786690116000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In vitro and in silico evaluation of the synergistic effect of Cytarabine and Zataria multiflora Boiss extract on pre-B acute lymphoblastic leukemia cells (NALM-6 cell line)"],"prefix":"10.1007","volume":"43","author":[{"given":"Niloofar","family":"Pilehvari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Fatemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahla","family":"Lashkari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajar Mardani","family":"Valandani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Hossein","family":"Ashoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roohollah Mirzaee","family":"Khalilabadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"3353_CR1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41572-024-00525-x","volume":"10","author":"L Pagliaro","year":"2024","unstructured":"Pagliaro L, Chen S-J, Herranz D, Mecucci C, Harrison CJ, Mullighan CG, et al. Acute lymphoblastic leukaemia. Nat Reviews Disease Primers. 2024;10:41.","journal-title":"Nat Reviews Disease Primers"},{"key":"3353_CR2","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1007\/s12098-023-04635-4","volume":"91","author":"J Sidhu","year":"2024","unstructured":"Sidhu J, Gogoi MP, Krishnan S, Saha V. Relapsed acute lymphoblastic leukemia. Indian J Pediatr. 2024;91:158\u201367.","journal-title":"Indian J Pediatr"},{"key":"3353_CR3","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.3390\/cancers14082021","volume":"14","author":"M Malczewska","year":"2022","unstructured":"Malczewska M, Ko\u015bmider K, Bednarz K, Ostapi\u0144ska K, Lejman M, Zawitkowska J. Recent advances in treatment options for childhood acute lymphoblastic leukemia. Cancers. 2022;14:2021.","journal-title":"Cancers"},{"key":"3353_CR4","doi-asserted-by":"publisher","first-page":"3346","DOI":"10.3390\/cancers15133346","volume":"15","author":"A Aureli","year":"2023","unstructured":"Aureli A, Marziani B, Venditti A, Sconocchia T, Sconocchia G. Acute lymphoblastic leukemia immunotherapy treatment: now, next, and beyond. Cancers. 2023;15:3346.","journal-title":"Cancers"},{"key":"3353_CR5","doi-asserted-by":"publisher","first-page":"966","DOI":"10.3390\/cancers13050966","volume":"13","author":"R Di Francia","year":"2021","unstructured":"Di Francia R, Crisci S, De Monaco A, Cafiero C, Re A, Iaccarino G, et al. Response and toxicity to cytarabine therapy in leukemia and lymphoma: from dose puzzle to pharmacogenomic biomarkers. Cancers. 2021;13:966.","journal-title":"Cancers"},{"key":"3353_CR6","doi-asserted-by":"publisher","first-page":"3565","DOI":"10.1007\/s00210-023-02865-z","volume":"397","author":"N Jan","year":"2024","unstructured":"Jan N, Shah H, Khan S, Nasar F, Madni A, Badshah SF, et al. Old drug, new tricks: polymer-based nanoscale systems for effective cytarabine delivery. Naunyn Schmiedebergs Arch Pharmacol. 2024;397:3565\u201384.","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"3353_CR7","doi-asserted-by":"publisher","first-page":"3067","DOI":"10.3390\/ijms23063067","volume":"23","author":"K J\u0119draszek","year":"2022","unstructured":"J\u0119draszek K, Malczewska M, Parysek-Wojcik K, Lejman M. Resistance mechanisms in pediatric B-cell acute lymphoblastic leukemia. Int J Mol Sci. 2022;23:3067.","journal-title":"Int J Mol Sci"},{"key":"3353_CR8","doi-asserted-by":"publisher","first-page":"11362","DOI":"10.3390\/ijms262311362","volume":"26","author":"MM Marrapodi","year":"2025","unstructured":"Marrapodi MM, Di Paola A, Di Feo G, Di Domenico O, Di Martino M, Argenziano L, et al. Novel Therapeutic Approaches in Pediatric Acute Lymphoblastic Leukemia. Int J Mol Sci. 2025;26:11362.","journal-title":"Int J Mol Sci"},{"key":"3353_CR9","doi-asserted-by":"publisher","first-page":"3058","DOI":"10.1080\/01635581.2022.2069274","volume":"74","author":"CX Ng","year":"2022","unstructured":"Ng CX, Affendi MM, Chong PP, Lee SH. The potential of plant-derived extracts and compounds to augment anticancer effects of chemotherapeutic drugs. Nutr Cancer. 2022;74:3058\u201376.","journal-title":"Nutr Cancer"},{"key":"3353_CR10","doi-asserted-by":"publisher","first-page":"1229760","DOI":"10.3389\/fmolb.2023.1229760","volume":"10","author":"CM Ar\u00e9valo","year":"2023","unstructured":"Ar\u00e9valo CM, Cruz-Rodriguez N, Quijano S, Fiorentino S. Plant-derived extracts and metabolic modulation in leukemia: A promising approach to overcome treatment resistance. Front Mol Biosci. 2023;10:1229760.","journal-title":"Front Mol Biosci"},{"key":"3353_CR11","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1007\/s12032-025-03104-6","volume":"42","author":"M Abdelkarim","year":"2025","unstructured":"Abdelkarim M, Kharrat R, Lakhal FB, Sioua H, Limam I, N\u00e9ji HB, et al. Ex vivo evaluation of Allium sativum extract on acute myeloid leukemia cells and leukemia stem cell populations. Med Oncol. 2025;42:536.","journal-title":"Med Oncol"},{"key":"3353_CR12","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1007\/s12032-024-02453-y","volume":"41","author":"R Kharrat","year":"2024","unstructured":"Kharrat R, Lakhal FB, Souia H, Limam I, Naji HB, Abdelkarim M. Anticancer effects of Artemisia campestris extract on acute myeloid leukemia cells: an ex vivo study. Med Oncol. 2024;41:206.","journal-title":"Med Oncol"},{"key":"3353_CR13","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1016\/j.jep.2012.12.018","volume":"145","author":"H Sajed","year":"2013","unstructured":"Sajed H, Sahebkar A, Iranshahi M. Zataria multiflora Boiss.(Shirazi thyme)\u2014an ancient condiment with modern pharmaceutical uses. J Ethnopharmacol. 2013;145:686\u201398.","journal-title":"J Ethnopharmacol"},{"key":"3353_CR14","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1111\/fcp.12331","volume":"32","author":"MR Khazdair","year":"2018","unstructured":"Khazdair MR, Ghorani V, Alavinezhad A, Boskabady MH. Pharmacological effects of Zataria multiflora Boiss L. and its constituents focus on their anti-inflammatory, antioxidant, and immunomodulatory effects. Fundam Clin Pharmacol. 2018;32:26\u201350.","journal-title":"Fundam Clin Pharmacol"},{"key":"3353_CR15","doi-asserted-by":"publisher","first-page":"12657","DOI":"10.1038\/s41598-022-16943-4","volume":"12","author":"M Lashkari","year":"2022","unstructured":"Lashkari M, Fatemi A, Valandani HM, Khalilabadi RM. Promising anti-leukemic effect of Zataria multiflora extract in combination with doxorubicin to combat acute lymphoblastic leukemia cells (Nalm-6)(in vitro and in silico). Sci Rep. 2022;12:12657.","journal-title":"Sci Rep"},{"key":"3353_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11033-025-11106-w","volume":"52","author":"S Mostajeran","year":"2025","unstructured":"Mostajeran S, Ehsan M, Lashkari M, Valandani HM, Fatemi A, Bazi A, et al. Zataria multiflora extract enhances imatinib-induced cytotoxicity in chronic myeloid leukemia and multiple myeloma cells. Mol Biol Rep. 2025;52:1\u201313.","journal-title":"Mol Biol Rep"},{"key":"3353_CR17","doi-asserted-by":"publisher","first-page":"43","DOI":"10.30699\/jambs.26.119.43","volume":"26","author":"I Baluchi","year":"2018","unstructured":"Baluchi I, Anani H, Farsinejad A, Fatemi A. The antitumoral activity of Zataria multiflora methanolic extract on acute promyelocytic leukemia cell line; NB4. J Adv Med Biomedical Res. 2018;26:43\u20137.","journal-title":"J Adv Med Biomedical Res"},{"key":"3353_CR18","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.3390\/genes12081188","volume":"12","author":"MY Yik","year":"2021","unstructured":"Yik MY, Azlan A, Rajasegaran Y, Rosli A, Yusoff NM, Moses EJ. Mechanism of human telomerase reverse transcriptase (hTERT) regulation and clinical impacts in leukemia. Genes. 2021;12:1188.","journal-title":"Genes"},{"key":"3353_CR19","doi-asserted-by":"publisher","first-page":"e701","DOI":"10.1097\/HS9.0000000000000701","volume":"6","author":"H Hohtari","year":"2022","unstructured":"Hohtari H, Kankainen M, Adnan-Awad S, Yadav B, Potdar S, Ianevski A, et al. Targeting apoptosis pathways with BCL2 and MDM2 inhibitors in adult B-cell acute lymphoblastic leukemia. HemaSphere. 2022;6:e701.","journal-title":"HemaSphere"},{"key":"3353_CR20","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.3390\/cancers13071536","volume":"13","author":"A Pastorczak","year":"2021","unstructured":"Pastorczak A, Domka K, Fidyt K, Poprzeczko M, Firczuk M. Mechanisms of immune evasion in acute lymphoblastic leukemia. Cancers. 2021;13:1536.","journal-title":"Cancers"},{"key":"3353_CR21","doi-asserted-by":"publisher","first-page":"5005","DOI":"10.3390\/ijms23095005","volume":"23","author":"N Koo","year":"2022","unstructured":"Koo N, Sharma AK, Narayan S. Therapeutics targeting p53-MDM2 interaction to induce cancer cell death. Int J Mol Sci. 2022;23:5005.","journal-title":"Int J Mol Sci"},{"key":"3353_CR22","first-page":"1397","volume":"23","author":"I Ramli","year":"2024","unstructured":"Ramli I, Cheriet T, Posadino AM, Giordo R, Fenu G, Nwachukwu KC, et al. Modulating the p53-MDM2 pathway: the therapeutic potential of natural compounds in cancer treatment. EXCLI J. 2024;23:1397.","journal-title":"EXCLI J"},{"key":"3353_CR23","doi-asserted-by":"publisher","first-page":"103792","DOI":"10.1016\/j.xphs.2025.103792","volume":"114","author":"MH Ashoub","year":"2025","unstructured":"Ashoub MH, Golestani A, Amiri M, Razavi R, Farsinejad A. pH-sensitive sulfasalazine release from green-synthesized mesoporous Fe3O4@ SiO2 nanocomposites using Opuntia ficus-indica extract. J Pharm Sci. 2025;114:103792.","journal-title":"J Pharm Sci"},{"key":"3353_CR24","doi-asserted-by":"publisher","first-page":"25743","DOI":"10.1038\/s41598-025-11532-7","volume":"15","author":"AH Alzaidy","year":"2025","unstructured":"Alzaidy AH, Ganduh SH, Abed MJ, Dawi EA, Jasim LS, Ashoub MH. Microwave assisted solvothermal green synthesis of Fe3O4 nanoparticles using sea buckthorn for multiple myeloma and monocytic leukemia treatment. Sci Rep. 2025;15:25743.","journal-title":"Sci Rep"},{"key":"3353_CR25","doi-asserted-by":"publisher","first-page":"3083","DOI":"10.1038\/s41598-025-85329-z","volume":"15","author":"MH Ashoub","year":"2025","unstructured":"Ashoub MH, Afgar A, Farsinejad A, Razavi R, Anvari S, Fatemi A. siRNA-mediated inhibition of hTERT enhances the effects of curcumin in promoting cell death in precursor-B acute lymphoblastic leukemia cells: an in silico and in vitro study. Sci Rep. 2025;15:3083.","journal-title":"Sci Rep"},{"key":"3353_CR26","doi-asserted-by":"publisher","first-page":"2796","DOI":"10.1007\/s10528-023-10565-9","volume":"62","author":"F Yari","year":"2024","unstructured":"Yari F, Ashoub MH, Amirizadeh N, Nikougoftar M, valandani HM, Khalilabadi RM. Differential Expression of the hTERT Gene in Umbilical Cord-Derived Mesenchymal Stem Cells Cocultured with B Cell Precursor Leukemia Cell Microparticles or CD41+\/CD61\u2009+\u2009Platelet Microparticles. Biochem Genet. 2024;62:2796\u2013809.","journal-title":"Biochem Genet"},{"key":"3353_CR27","doi-asserted-by":"publisher","first-page":"e71335","DOI":"10.1002\/cam4.71335","volume":"14","author":"Y Tian","year":"2025","unstructured":"Tian Y, Ni B, Cai D, Wang J, Zhou J, Song M, et al. Integrating Nature Into Oncology: Enhancing Hematological Malignancies Therapies With Natural Medicine. Cancer Med. 2025;14:e71335.","journal-title":"Cancer Med"},{"key":"3353_CR28","doi-asserted-by":"publisher","first-page":"1008893","DOI":"10.3389\/fnut.2022.1008893","volume":"9","author":"OO Izuegbuna","year":"2022","unstructured":"Izuegbuna OO, Polyphenols. Chemoprevention and therapeutic potentials in hematological malignancies. Front Nutr. 2022;9:1008893.","journal-title":"Front Nutr"},{"key":"3353_CR29","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.3892\/etm.2017.4620","volume":"14","author":"R Deng","year":"2017","unstructured":"Deng R, Fan FY, Yi H, Fu L, Zeng Y, Wang Y, et al. Cytotoxic T lymphocytes promote cytarabine-induced acute myeloid leukemia cell apoptosis via inhibiting Bcl-2 expression. Experimental therapeutic Med. 2017;14:1081\u20135.","journal-title":"Experimental therapeutic Med"},{"key":"3353_CR30","doi-asserted-by":"publisher","first-page":"353","DOI":"10.2174\/18715206113139990091","volume":"14","author":"K Kontos","year":"2014","unstructured":"Kontos K, Christodoulou C, Scorilas M-I. Apoptosis-related BCL2-family members: Key players in chemotherapy. Anti-Cancer Agents Med Chemistry-Anti-Cancer Agents). 2014;14:353\u201374.","journal-title":"Anti-Cancer Agents Med Chemistry-Anti-Cancer Agents)"},{"key":"3353_CR31","doi-asserted-by":"publisher","first-page":"427","DOI":"10.3390\/antiox13040427","volume":"13","author":"E Bartoszewska","year":"2024","unstructured":"Bartoszewska E, Molik K, Wo\u017aniak M, Choroma\u0144ska A. Telomerase inhibition in the treatment of leukemia: a comprehensive review. Antioxidants. 2024;13:427.","journal-title":"Antioxidants"},{"key":"3353_CR32","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3390\/cancers18020185","volume":"18","author":"F Merhi","year":"2026","unstructured":"Merhi F, Dauzonne D, Bauvois B. Implementation of Natural Products and Derivatives in Acute Myeloid Leukemia Management: Current Treatments, Clinical Trials and Future Directions. Cancers. 2026;18:185.","journal-title":"Cancers"},{"key":"3353_CR33","doi-asserted-by":"publisher","first-page":"2709","DOI":"10.3390\/molecules26092709","volume":"26","author":"C Cotoraci","year":"2021","unstructured":"Cotoraci C, Ciceu A, Sasu A, Miutescu E, Hermenean A. The anti-leukemic activity of natural compounds. Molecules. 2021;26:2709.","journal-title":"Molecules"},{"key":"3353_CR34","doi-asserted-by":"publisher","first-page":"984","DOI":"10.3390\/cancers16050984","volume":"16","author":"R Kim","year":"2024","unstructured":"Kim R, Kin T, Beck WT. Impact of complex apoptotic signaling pathways on cancer cell sensitivity to therapy. Cancers. 2024;16:984.","journal-title":"Cancers"},{"key":"3353_CR35","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s10555-024-10172-z","volume":"43","author":"GR Bhat","year":"2024","unstructured":"Bhat GR, Sethi I, Sadida HQ, Rah B, Mir R, Algehainy N, et al. Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance. Cancer Metastasis Rev. 2024;43:197\u2013228.","journal-title":"Cancer Metastasis Rev"},{"key":"3353_CR36","doi-asserted-by":"crossref","unstructured":"Haferssas D, Dubuissez M, Barrera-Chimal J, Messmer C, Affar EB, Larriv\u00e9e B et al. FLT4 activation promotes acute lymphoid leukemia survival through stabilization of MDM2\/MDMX and inactivation of p53. Oncogenesis. 2025;14:14.","DOI":"10.1038\/s41389-025-00552-7"},{"key":"3353_CR37","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3892\/br.2025.1943","volume":"22","author":"A Kimura","year":"2025","unstructured":"Kimura A, Tsubaki M, Obana T, Matsuo T, Komori R, Nagai N, et al. MDM2 inhibitors induce apoptosis by suppressing MDM2 and enhancing p53, Bax, Puma and Noxa expression levels in imatinib\u2013resistant chronic myeloid leukemia cells. Biomedical Rep. 2025;22:65.","journal-title":"Biomedical Rep"},{"key":"3353_CR38","doi-asserted-by":"crossref","unstructured":"Khan S, Anwar S, Choudhury A, Mohammad T, Hassan MI. Validation of drug targets using molecular methodologies and enzymatic activity assays for validation of inhibitory potential. Bacterial Enzymes as Targets for Drug Discovery. Elsevier; 2025. pp. 91\u2013112.","DOI":"10.1016\/B978-0-443-22222-1.00007-6"},{"key":"3353_CR39","unstructured":"Wang T, Chen S, Wang Y, Zhang Y, Song X, Bi Z et al. From in silico to in vitro: a comprehensive guide to validating bioinformatics findings. arXiv preprint arXiv:250203478 2025."}],"container-title":["Medical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-026-03353-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12032-026-03353-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-026-03353-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T03:20:08Z","timestamp":1788924008000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12032-026-03353-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["3353"],"URL":"https:\/\/doi.org\/10.1007\/s12032-026-03353-z","relation":{},"ISSN":["1559-131X"],"issn-type":[{"value":"1559-131X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]},"assertion":[{"value":"22 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was approved by Kerman University of Medical Science Ethical & Research Committee (ethical code: IR.KMU.REC.1397.612). The volunteers were informed about the objective and procedure of the study and those who were willing to participate, donate blood sample, and sign an informed consent were recruited. All methods were performed in accordance with relevant guidelines and applicable regulations.","order":1,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Consent to publish","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","label":"Competing intewrests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"244"}}