{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:36:32Z","timestamp":1790015792542,"version":"4.0.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:00:00Z","timestamp":1607644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81502582, U1603125, 31670770"],"award-info":[{"award-number":["81502582, U1603125, 31670770"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["N182004002, N141008001-8"],"award-info":[{"award-number":["N182004002, N141008001-8"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013284","name":"Program for Jilin University Science and Technology Innovative Research Team","doi-asserted-by":"publisher","award":["2017TD-28"],"award-info":[{"award-number":["2017TD-28"]}],"id":[{"id":"10.13039\/501100013284","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Magnesium, the second most predominant intracellular cation, plays a crucial role in many physiological functions; magnesium-based biomaterials have been widely used in clinical application. In a variety of cancer types, the high intracellular concentration of magnesium contributes to cancer initiation and progression. Therefore, we initiated this study to investigate the likelihood of confounding magnesium with cancer therapy. In this study, the anti-tumor activity of magnesium and underlying mechanisms were assessed in bladder cancer both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. The results indicated that the proliferation of bladder cancer cells was inhibited by treatment with a high concentration of MgCl<jats:sub>2<\/jats:sub> or MgSO<jats:sub>4<\/jats:sub>. The apoptosis, G0\/G1 cell cycle arrest, autophagy, and ER stress were promoted following treatment with MgCl<jats:sub>2<\/jats:sub>. However, the migratory ability of MgCl<jats:sub>2<\/jats:sub> treated cells was similar to that of control cells, as revealed by the trans-well assay. Besides, no significant difference was observed in the proportion of CD44 or CD133 positive cells between the control and MgCl<jats:sub>2<\/jats:sub> treated cells. Thus, to improve the therapeutic effect of magnesium, VPA was used to treat cancer cells in combination with MgCl<jats:sub>2<\/jats:sub>. As expected, combination treatment with MgCl<jats:sub>2<\/jats:sub> and VPA could markedly reduce proliferation, migration, and <jats:italic>in vivo<\/jats:italic> tumorigenicity of UC3 cells. Moreover, the Wnt signaling was down-regulated, and ERK signaling was activated in the cells treated with combination treatment. In conclusion, the accurate utilization of MgCl<jats:sub>2<\/jats:sub> in targeting autophagy might be beneficial in cancer therapy. Although further studies are warranted, the combination treatment of MgCl<jats:sub>2<\/jats:sub> with VPA is an effective strategy to improve the outcome of chemotherapy.<\/jats:p>","DOI":"10.3389\/fonc.2020.589112","type":"journal-article","created":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T08:27:03Z","timestamp":1607675223000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Magnesium in Combinatorial With Valproic Acid Suppressed the Proliferation and Migration of Human Bladder Cancer Cells"],"prefix":"10.3389","volume":"10","author":[{"given":"Tianye","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangfu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuping","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaowu","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongye","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03262330","article-title":"The health economics of bladder cancer: a comprehensive review of the published literature","volume":"21","author":"Botteman","year":"2003","journal-title":"Pharmacoeconomics"},{"key":"B3","article-title":"Chemotherapy against bladder cancer in geriatric patients","volume":"75","author":"Nagao","year":"2017","journal-title":"Nihon Rinsho"},{"key":"B4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s11864-015-0376-y","article-title":"Chemotherapy for Muscle-Invasive Bladder Cancer","volume":"17","author":"Trenta","year":"2016","journal-title":"Curr Treat Options Oncol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s11912-016-0512-2","article-title":"Improving Systemic Chemotherapy for Bladder Cancer","volume":"18","author":"Rose","year":"2016","journal-title":"Curr Oncol Rep"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2017.82","article-title":"Landmarks in the treatment of muscle-invasive bladder cancer","volume":"14","author":"Lobo","year":"2017","journal-title":"Nat Rev Urol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/nrc.2016.108","article-title":"Cancer nanomedicine: progress, challenges and opportunities","volume":"17","author":"Shi","year":"2017","journal-title":"Nat Rev Cancer"},{"key":"B8","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.biomaterials.2015.09.030","article-title":"In vivo dual-targeted chemotherapy of drug resistant cancer by rationally designed nanocarrier","volume":"75","author":"Wang","year":"2016","journal-title":"Biomaterials"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.11.022","article-title":"Mg(II)-Catechin nanoparticles delivering siRNA targeting EIF5A2 inhibit bladder cancer cell growth in vitro and in vivo","volume":"81","author":"Chen","year":"2016","journal-title":"Biomaterials"},{"key":"B10","doi-asserted-by":"publisher","first-page":"S92","DOI":"10.1684\/mrh.2011.0285","article-title":"Magnesium and cancer: a dangerous liason","volume":"24","author":"Castiglioni","year":"2011","journal-title":"Magnes Res"},{"key":"B11","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1042\/CS20070129","article-title":"Cell (patho)physiology of magnesium","volume":"114","author":"Wolf","year":"2008","journal-title":"Clin Sci (Lond)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/BF01076575","article-title":"Second messenger role of magnesium in pancreatic acinar cells of the rat","author":"Singh","year":"1995","journal-title":"Mol Cell Biochem"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/bs.acc.2015.10.002","article-title":"The Importance of Magnesium in the Human Body: A Systematic Literature Review","volume":"73","author":"Glasdam","year":"2016","journal-title":"Adv Clin Chem"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2010.02.028","article-title":"The history of biodegradable magnesium implants: a review","volume":"6","author":"Witte","year":"2010","journal-title":"Acta Biomater"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2018.07.028","article-title":"Molecular and cellular mechanisms for zoledronic acid-loaded magnesium-strontium alloys to inhibit giant cell tumors of bone","volume":"77","author":"Li","year":"2018","journal-title":"Acta Biomater"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.b.34375","article-title":"Cytotoxicity of biodegradable magnesium alloy WE43 to tumor cells in vitro: Bioresorbable implants with antitumor activity","volume":"108","author":"Anisimova","year":"2019","journal-title":"J BioMed Mater Res B Appl Biomater"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.msec.2015.12.043","article-title":"Porous biodegradable EW62 medical implants resist tumor cell growth","volume":"61","author":"Hakimi","year":"2016","journal-title":"Mater Sci Eng C Mater Biol Appl"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcx186","article-title":"Chronic magnesium deficiency and human disease; time for reappraisal","volume":"111","author":"Ismail","year":"2018","journal-title":"QJM"},{"key":"B19","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/S1040-8428(02)00006-9","article-title":"Magnesium-DNA interactions and the possible relation of magnesium to carcinogenesis. Irradiation and free radicals","volume":"42","author":"Anastassopoulou","year":"2002","journal-title":"Crit Rev Oncol Hematol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-017-1207-8","article-title":"Magnesium in Breast Cancer: What Is Its Influence on the Progression of This Disease","volume":"184","author":"Mendes","year":"2018","journal-title":"Biol Trace Elem Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.5RI0116-013RR","article-title":"Combinatorial approach to cancer immunotherapy: strength in numbers","volume":"100","author":"Vilgelm","year":"2016","journal-title":"J Leukoc Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2284","article-title":"Combinatorial drug therapy for cancer in the post-genomic era","volume":"30","author":"Al-Lazikani","year":"2012","journal-title":"Nat Biotechnol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2007.11.003","article-title":"Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors","volume":"34","author":"Duenas-Gonzalez","year":"2008","journal-title":"Cancer Treat Rev"},{"key":"B24","doi-asserted-by":"publisher","first-page":"5039","DOI":"10.1038\/s41598-019-41527-0","article-title":"Carfilzomib enhances cisplatin-induced apoptosis in SK-N-BE(2)-M17 human neuroblastoma cells","volume":"9","author":"Lee","year":"2019","journal-title":"Sci Rep"},{"key":"B25","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/(SICI)1097-4644(1997)27+<35::AID-JCB8>3.0.CO;2-2","article-title":"Chemoprevention by naturally occurring and synthetic agents in oral, liver, and large bowel carcinogenesis","volume":"27","author":"Mori","year":"1997","journal-title":"J Cell Biochem Suppl"},{"key":"B26","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1615\/CritRevEukaryotGeneExpr.v26.i1.60","article-title":"Dual Role of p21 in the Progression of Cancer and Its Treatment","volume":"26","author":"Parveen","year":"2016","journal-title":"Crit Rev Eukaryot Gene Expr"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.3390\/cancers11081178","article-title":"p21 in Cancer Research","volume":"11","author":"Shamloo","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.53","article-title":"Targeting autophagy in cancer","volume":"17","author":"Levy","year":"2017","journal-title":"Nat Rev Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.semcancer.2019.08.020","article-title":"Pro-survival Autophagy: An Emerging Candidate of Tumor Progression through Maintaining Hallmarks of Cancer","volume":"66","author":"Das","year":"2019","journal-title":"Semin Cancer Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4402039","article-title":"Autophagy delays apoptotic death in breast cancer cells following DNA damage","volume":"14","author":"Abedin","year":"2007","journal-title":"Cell Death Differ"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e838","DOI":"10.1038\/cddis.2013.350","article-title":"Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment","volume":"4","author":"Sui","year":"2013","journal-title":"Cell Death Dis"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25785","article-title":"Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress","volume":"232","author":"Song","year":"2017","journal-title":"J Cell Physiol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26137","article-title":"Crosstalk of ER stress-mediated autophagy and ER-phagy: Involvement of UPR and the core autophagy machinery","volume":"233","author":"Song","year":"2018","journal-title":"J Cell Physiol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2017.00078","article-title":"Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate","volume":"7","author":"Corazzari","year":"2017","journal-title":"Front Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.12.017","article-title":"How IRE1 reacts to ER stress","volume":"132","author":"Ron","year":"2008","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.304","article-title":"Wnt signaling in cancer","volume":"36","author":"Zhan","year":"2017","journal-title":"Oncogene"},{"key":"B37","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.ctrv.2017.11.002","article-title":"Targeting the Wnt\/beta-catenin pathway in cancer: Update on effectors and inhibitors","volume":"62","author":"Krishnamurthy","year":"2018","journal-title":"Cancer Treat Rev"},{"key":"B38","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/s13045-020-00949-4","article-title":"and AMPK signalings: interplay and implication in targeted cancer therapy","volume":"13","author":"Yuan","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2530","DOI":"10.3390\/ijms20102530","article-title":"Biological Rationale for Targeting MEK\/ERK Pathways in Anti-Cancer Therapy and to Potentiate Tumour Responses to Radiation","volume":"20","author":"Marampon","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.3390\/ijms20102505","article-title":"ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer","volume":"20","author":"Salaroglio","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B41","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1186\/s12885-020-06947-6","article-title":"Upregulation of pERK and c-JUN by gamma-tocotrienol and not alpha-tocopherol are essential to the differential effect on apoptosis in prostate cancer cells","volume":"20","author":"Moore","year":"2020","journal-title":"BMC Cancer"},{"key":"B42","article-title":"Overexpression of BPIFB1 promotes apoptosis and inhibits proliferation via the MEK\/ERK signal pathway in nasopharyngeal carcinoma","volume":"12","author":"Xu","year":"2019","journal-title":"Int J Clin Exp Pathol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.3390\/cancers11081136","article-title":"EMT and Stemness-Key Players in Pancreatic Cancer Stem Cells","volume":"11","author":"Rodriguez-Aznar","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2108","article-title":"Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science","volume":"8","author":"Xiang","year":"2019","journal-title":"Cancer Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19934","article-title":"Reduced E-cadherin expression is correlated with poor prognosis in patients with bladder cancer: a systematic review and meta-analysis","volume":"8","author":"Xie","year":"2017","journal-title":"Oncotarget"},{"key":"B46","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1002\/1878-0261.12096","article-title":"Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness","volume":"11","author":"Liao","year":"2017","journal-title":"Mol Oncol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19112","article-title":"Bladder cancer stem cells: clonal origin and therapeutic perspectives","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"B48","article-title":"MAGE-A3 is highly expressed in a cancer stem cell-like side population of bladder cancer cells","volume":"7","author":"Yin","year":"2014","journal-title":"Int J Clin Exp Pathol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.07.020","article-title":"P120 and E-cadherin: Double-edged swords in tumor metastasis","volume":"60","author":"Venhuizen","year":"2019","journal-title":"Semin Cancer Biol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2013.1565","article-title":"Inhibitory effect of valproic acid on bladder cancer in combination with chemotherapeutic agents in vitro and in vivo","volume":"6","author":"Wang","year":"2013","journal-title":"Oncol Lett"},{"key":"B51","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1002\/2211-5463.12223","article-title":"Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells","volume":"7","author":"Liu","year":"2017","journal-title":"FEBS Open Bio"},{"key":"B52","doi-asserted-by":"crossref","DOI":"10.1111\/fcp.12608","article-title":"Valproic acid reverses Sorafenib resistance through inhibiting activated Notch\/Akt signaling pathway in HCC","volume-title":"Fundam Clin Pharmacol","author":"Yang","year":"2020"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00732","article-title":"Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance","volume":"8","author":"Iannelli","year":"2020","journal-title":"Front Cell Dev Biol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2020.589112\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T08:27:08Z","timestamp":1607675228000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2020.589112\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,11]]},"references-count":53,"alternative-id":["10.3389\/fonc.2020.589112"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2020.589112","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,11]]},"article-number":"589112"}}