{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:34:28Z","timestamp":1790714068702,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science, Research and Innovation Fund (NSRF)","award":["MED6701155S"],"award-info":[{"award-number":["MED6701155S"]}]},{"name":"Prince of Songkla University","award":["MED6701155S"],"award-info":[{"award-number":["MED6701155S"]}]},{"name":"Faculty of Medicine, Prince of Songkla University","award":["MED6701155S"],"award-info":[{"award-number":["MED6701155S"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Bone marrow mesenchymal stem cells (BM-MSCs) are significant in chemo- and radiotherapy resistance. Previous research has focused on BM-MSCs, demonstrating their functional involvement in cancer progression as mediators in the tumor microenvironment. They play multiple roles in tumorigenesis, angiogenesis, and metastasis. BM-MSC-derived exosomes (BM-MSCs-exo) are small vesicles, typically 50\u2013300 nm in diameter, isolated from BM-MSCs. Some studies have demonstrated the tumor-suppressive effects of BM-MSCs-exo. Objective: This study aimed to investigate their role in modulating the impact of chemoradiotherapy (CRT) in different types of cervical cancer spheroid cells. Methods: The spheroids after treatment were subject to size measurement, cell viability, and caspase activity. Then, the molecular mechanism was elucidated by Western blot analysis. Results: We observed a reduction in spheroid size and an increase in cell death in HeLa spheroids, while no significant changes in size or cell viability were found in SiHa spheroids. At the molecular level, CRT treatment combined with BM-MSCs-exo in HeLa spheroids induced apoptosis through the activation of the NF-\u03baB pathway, specifically via the NF-\u03baB1 (P50) transcription factor, leading to the upregulation of apoptosis-related molecules. In contrast, CRT combined with BM-MSCs-exo in SiHa spheroids exhibited an opposing effect: although cellular viability decreased, caspase activity also decreased, which correlated with increased HSP27 expression and the subsequent downregulation of apoptotic molecules. Conclusion: Our study provides deeper insight into the potential of BM-MSCs-exo in cervical cancer treatment, supporting the development of more effective and safer therapeutic strategies for clinical application.<\/jats:p>","DOI":"10.3390\/ph18071050","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T11:25:17Z","timestamp":1752751517000},"page":"1050","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Modulate Chemoradiotherapy Response in Cervical Cancer Spheroids"],"prefix":"10.3390","volume":"18","author":[{"given":"Kesara","family":"Nittayaboon","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyatida","family":"Molika","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rassanee","family":"Bissanum","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Thailand"},{"name":"Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7621-4510","authenticated-orcid":false,"given":"Kittinun","family":"Leetanaporn","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Thailand"},{"name":"Translational Medicine Research Center, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nipha","family":"Chumsuwan","sequence":"additional","affiliation":[{"name":"Department of Radiology, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Thailand"},{"name":"Division of Therapeutic Radiology and Oncology, Department of Radiology, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-0079","authenticated-orcid":false,"given":"Raphatphorn","family":"Navakanitworakul","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hmadcha, A., Martin-Montalvo, A., Gauthier, B.R., Soria, B., and Capilla-Gonzalez, V. (2020). Therapeutic potential of mesenchymal stem cells for cancer therapy. Front. Bioeng. Biotechnol., 8.","DOI":"10.3389\/fbioe.2020.00043"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1002\/sctm.17-0138","article-title":"Concise review: Cancer cells, cancer stem cells, and mesenchymal stem cells: Influence in cancer development","volume":"6","author":"Papaccio","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14637","DOI":"10.1007\/s13277-016-5319-0","article-title":"Bone marrow-derived mesenchymal stem cells increase drug resistance in CD133-expressing gastric cancer cells by regulating the PI3K\/AKT pathway","volume":"37","author":"Ji","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1758139","DOI":"10.1155\/2017\/1758139","article-title":"Mesenchymal stem cell-derived extracellular vesicles: Roles in tumor growth, progression, and drug resistance","volume":"2017","author":"Zhang","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1080\/15384101.2015.1005530","article-title":"Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer","volume":"14","author":"Ji","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"193","DOI":"10.7150\/ijms.3635","article-title":"Cancer and radiation therapy: Current advances and future directions","volume":"9","author":"Baskar","year":"2012","journal-title":"Int. J. Med. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0140-6736(92)90218-R","article-title":"Biological basis for radiation therapy for cancer","volume":"339","author":"Withers","year":"1992","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Akhunzianov, A.A., Rozhina, E.V., Filina, Y.V., Rizvanov, A.A., and Miftakhova, R.R. (2025). Resistance to Radiotherapy in Cancer. Diseases, 13.","DOI":"10.3390\/diseases13010022"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lee, J.-K., Park, S.-R., Jung, B.-K., Jeon, Y.-K., Lee, Y.-S., Kim, M.-K., Kim, Y.-G., Jang, J.-Y., Kim, C.-W., and Shi, S. (2013). Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084256"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Shams, F., Pourjabbar, B., Hashemi, N., Farahmandian, N., Golchin, A., Nuoroozi, G., and Rahimpour, A. (2023). Current progress in engineered and nano-engineered mesenchymal stem cells for cancer: From mechanisms to therapy. Biomed. Pharmacother., 167.","DOI":"10.1016\/j.biopha.2023.115505"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"609","DOI":"10.3892\/ijmm.2020.4634","article-title":"Exosomal microRNA-146a derived from mesenchymal stem cells increases the sensitivity of ovarian cancer cells to docetaxel and taxane via a LAMC2-mediated PI3K\/Akt axis","volume":"46","author":"Qiu","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s40164-021-00206-5","article-title":"MiRNA-mediated EMT and CSCs in cancer chemoresistance","volume":"10","author":"Dong","year":"2021","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1186\/s12943-022-01650-5","article-title":"Mesenchymal stem cell-derived exosomes in cancer therapy resistance: Recent advances and therapeutic potential","volume":"21","author":"Lin","year":"2022","journal-title":"Mol. Cancer."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13046-021-01834-9","article-title":"Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10","volume":"40","author":"Chen","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e42733","DOI":"10.1016\/j.heliyon.2025.e42733","article-title":"The role of miR-16 and miR-34a family in the regulation of cancers: A review","volume":"11","author":"Sadeghi","year":"2025","journal-title":"Heliyon"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"279","DOI":"10.32604\/Oncologie.2021.015969","article-title":"Growth and Invasion of 3D Spheroid Tumor of HeLa and CasKi Cervical Cancer Cells","volume":"23","author":"Muniandy","year":"2021","journal-title":"Oncologie"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Molika, P., Leetanaporn, K., Chiangjong, W., Choochuen, P., and Navakanitworakul, R. (2024). Proteomic Analysis Reveals Cadherin, Actin, and Focal Adhesion Molecule-Mediated Formation of Cervical Cancer Spheroids. Cells, 13.","DOI":"10.3390\/cells13232004"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines","volume":"7","author":"Witwer","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E968","DOI":"10.1073\/pnas.1521230113","article-title":"Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes","volume":"113","author":"Kowal","year":"2016","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.colsurfb.2011.05.013","article-title":"Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy","volume":"87","author":"Sokolova","year":"2011","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.nano.2011.04.003","article-title":"Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis","volume":"7","author":"Dragovic","year":"2011","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"27066","DOI":"10.3402\/jev.v4.27066","article-title":"Biological properties of extracellular vesicles and their physiological functions","volume":"4","author":"Siljander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"920161","DOI":"10.4061\/2010\/920161","article-title":"H2AX phosphorylation: Its role in DNA damage response and cancer therapy","volume":"2010","author":"Podhorecka","year":"2010","journal-title":"J. Nucleic Acids"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.molcel.2006.05.023","article-title":"Cell apoptosis: Requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3","volume":"23","author":"Lu","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"233","DOI":"10.4161\/cbt.2.3.373","article-title":"Histone H2AX in DNA damage and repair","volume":"2","author":"Sedelnikova","year":"2003","journal-title":"Cancer Biol. Ther."},{"key":"ref_26","first-page":"590764154","article-title":"NF-kB Signaling Pathway","volume":"13","author":"Du","year":"2022","journal-title":"Chemo-Radiat.-Resist. Cancer Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/jcp.10257","article-title":"BRCA1 gene in breast cancer","volume":"196","author":"Rosen","year":"2003","journal-title":"J. Cell Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1002\/1521-1878(200008)22:8<728::AID-BIES6>3.0.CO;2-B","article-title":"Roles of BRCA1 and its interacting proteins","volume":"22","author":"Deng","year":"2000","journal-title":"Bioessays"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33165","DOI":"10.1074\/jbc.M505124200","article-title":"BRCA1 interaction with human papillomavirus oncoproteins","volume":"280","author":"Zhang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wen, X., Liu, S., Cui, M., and Kanazawa, N. (2020). Effect of BRCA1 on the concurrent chemoradiotherapy resistance of cervical squamous cell carcinoma based on transcriptome sequencing analysis. Biomed. Res. Int., 2020.","DOI":"10.1155\/2020\/3598417"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12032-025-02632-5","article-title":"Bone marrow mesenchymal stem cells enrich breast cancer stem cell population via targeting metabolic pathways","volume":"42","author":"Movahed","year":"2025","journal-title":"Med. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.2147\/IJN.S487097","article-title":"Bone Marrow Mesenchymal Stem Cells-Derived Exosomes Inhibit Apoptosis of Pulmonary Microvascular Endothelial Cells in COPD Mice Through miR-30b\/Wnt5a Pathway","volume":"20","author":"Song","year":"2025","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1515\/biol-2022-0017","article-title":"Regulation of miR-30b in cancer development, apoptosis, and drug resistance","volume":"17","author":"Fu","year":"2022","journal-title":"Open Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"44","DOI":"10.3892\/etm.2020.9475","article-title":"Roles and regulatory mechanisms of miR-30b in cancer, cardiovascular disease, and metabolic disorders","volume":"21","author":"Zhang","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3526","DOI":"10.1111\/jcmm.17933","article-title":"Inhibitory role of bone marrow mesenchymal stem cells-derived exosome in non-small-cell lung cancer: microRNA-30b-5p, EZH2 and PI3K\/AKT pathway","volume":"27","author":"Wu","year":"2023","journal-title":"J. Cell Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.reth.2025.03.006","article-title":"MSC-derived extracellular vesicles: Precision miRNA delivery for overcoming cancer therapy resistance","volume":"29","author":"Goyal","year":"2025","journal-title":"Regen. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1089\/scd.2012.0304","article-title":"Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth","volume":"22","author":"Bruno","year":"2013","journal-title":"Stem Cells Dev."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Papadopoulos, K.S., Korkolopoulou, P., and Piperi, C. (2025). Exploring the Interaction of Tumor-Derived Exosomes and Mesenchymal Stem Cells in Tumor Biology. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073095"},{"key":"ref_39","first-page":"1649","article-title":"miR-199a-3p enhances cisplatin sensitivity of ovarian cancer cells by targeting ITGB8","volume":"39","author":"Cui","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.24976\/Discov.Med.202436185.121","article-title":"Proteomic Analysis of Butyrate-Resistant Colorectal Cancer-Derived Exosomes Reveals Potential Resistance to Anti-Cancer Drugs","volume":"36","author":"Nittayaboon","year":"2024","journal-title":"Discov. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Jeanmard, N., Bissanum, R., Sriplung, H., Charoenlappanit, S., Roytrakul, S., Navakanitworakul, R., and Mishra, S.K. (2023). Proteomic profiling of urinary extracellular vesicles differentiates breast cancer patients from healthy women. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0291574"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Monnamorn, L., Seree-Aphinan, C., Molika, P., Vichitkunakorn, P., Pattanapanyasat, K., Khwannimit, B., and Navakanitworakul, R. (2021). The concentration of large extracellular vesicles differentiates early septic shock from infection. Front. Med., 8.","DOI":"10.3389\/fmed.2021.724371"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/1050\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:11:20Z","timestamp":1760033480000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/1050"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ph18071050"],"URL":"https:\/\/doi.org\/10.3390\/ph18071050","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,17]]}}}