title: ZnCl2 sustains the adriamycin-induced cell death inhibited by high glucose.
abstract: Hyperglycemia, the condition of high blood glucose, is typical of diabetes and obesity and represents a significant clinical problem. The relationship between hyperglycemia and cancer risk has been established by several studies. Moreover, hyperglycemia has been shown to reduce cancer cell response to therapies, conferring resistance to drug-induced cell death. Therefore, counteracting the negative effects of hyperglycemia may positively improve the cancer cell death induced by chemotherapies. Recent studies showed that zinc supplementation may have beneficial effects on glycemic control. Here we aimed at evaluating whether ZnCl2 could counteract the high-glucose (HG) effects and consequently restore the drug-induced cancer cell death. At the molecular level we found that the HG-induced expression of genes known to be involved in chemoresistance (such as HIF-1α, GLUT1, and HK2 glycolytic genes, as well as NF-κB activity) was reduced by ZnCl2 treatment. In agreement, the adryamicin (ADR)-induced apoptotic cancer cell death was significantly impaired by HG and efficiently re-established by ZnCl2 cotreatment. Mechanistically, the ADR-induced c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) phosphorylation, inhibited by HG, was efficiently restored by ZnCl2. The JNK involvement in apoptotic cell death was assessed by the use of JNK dominant-negative expression vector that indeed impaired the ZnCl2 ability to restore drug-induced cell death in HG condition. Altogether, these findings indicate that ZnCl2 supplementation efficiently restored the drug-induced cancer cell death, inhibited by HG, by both sustaining JNK activation and counteracting the glycolytic pathway.
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.|Department of Medical, Oral and Biotechnological Sciences, Tumor Biology Section, University 'G. d'Annunzio', Chieti, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Garufi
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Trisciuoglio
authors.affiliation: Department of Experimental Medicine, Pasteur-Fondazione Cenci Bolognetti Institute, Sapienza University, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cirone
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.|Department of Medical, Oral and Biotechnological Sciences, Tumor Biology Section, University 'G. d'Annunzio', Chieti, Italy.
authors.forename: G
authors.initials: G
authors.lastname: D'Orazi
mesh_terms: D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000494:pharmacology*; D003847:Deoxyglucose / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D005947:Glucose / Q000633:toxicity*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017967:Zinc Compounds / Q000494:pharmacology*
chemical_list: D002712:Chlorides; D051272:Glucose Transporter Type 1; D016328:NF-kappa B; D017967:Zinc Compounds; D004317:Doxorubicin; C016837:zinc chloride; D003847:Deoxyglucose; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose