title: The beneficial effect of Zinc(II) on low-dose chemotherapeutic sensitivity involves p53 activation in wild-type p53-carrying colorectal cancer cells.
abstract: BACKGROUND
  Activation of wild-type p53 in response to genotoxic stress occurs through different mechanisms including protein conformation, posttranslational modifications, and nuclear localization, leading to DNA binding to sequence-specific promoters. Zinc ion plays a crucial role in stabilizing p53/DNA binding to induce canonical target genes. Mutant p53 proteins undergo protein misfolding that can be counteracted by zinc. However, whether zinc supplementation might have a beneficial antitumor effect in wild-type p53-carrying cells in combination with drugs, has not been addressed so far.
  
  
  METHODS
  In this study we compared the effect of two antitumor treatments: on the one hand wild-type p53-carrying colon cancer cells were treated with low and high doses of chemotherapeutic agent Adriamycin and, on the other hand, Adriamycin was used in combination with ZnCl2. Biochemical and molecular analyses were applied to evaluate p53 activity and biological outcomes in this setting. Finally, the effect of the different combination treatments were applied to assess tumor growth in vivo in tumor xenografts.
  
  
  RESULTS
  We found that low-dose Adriamycin did not induce p53 activation in wtp53-carrying colon cancer cells, unless in combination with ZnCl2. Mechanistically, ZnCl2 was a key determinant in inducing wtp53/DNA binding and transactivation of target genes in response to low-dose Adriamycin that used alone did not achieve such effects. Finally, in vivo studies, in a model of wtp53 colon cancer xenograft, show that low-dose Adriamycin did not induce tumor regression unless in combination with ZnCl2 that activated endogenous wtp53.
  
  
  CONCLUSIONS
  These results provide evidence that ZnCl2 might be a valuable adjuvant in chemotherapeutic regimens of colorectal cancer harboring wild-type p53, able to both activate p53 and reduce the amount of drugs for antitumor purposes.
authors: Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", 66013, Chieti, Italy. alessiagarufi@yahoo.it.|Translational Research Department, Regina Elena National Cancer Institute, 00158, Rome, Italy. alessiagarufi@yahoo.it.
authors: Alessia
authors: A
authors: Garufi
authors: Translational Research Department, Regina Elena National Cancer Institute, 00158, Rome, Italy. ubertini@ifo.it.
authors: Valentina
authors: V
authors: Ubertini
authors: Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), Roma, Italy. francesca.mancini@cnr.it.
authors: Francesca
authors: F
authors: Mancini
authors: Department of Surgical Sciences, Sapienza University, 00100, Rome, Italy. info@valeriodorazi.com.
authors: Valerio
authors: V
authors: D'Orazi
authors: Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", 66013, Chieti, Italy. silvia.baldari@yahoo.it.|Translational Research Department, Regina Elena National Cancer Institute, 00158, Rome, Italy. silvia.baldari@yahoo.it.
authors: Silvia
authors: S
authors: Baldari
authors: Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), Roma, Italy. fabiola.moretti@cnr.it.
authors: Fabiola
authors: F
authors: Moretti
authors: Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, 00158, Rome, Italy. bossi@ifo.it.
authors: Gianluca
authors: G
authors: Bossi
authors: Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", 66013, Chieti, Italy. gdorazi@unich.it.|Translational Research Department, Regina Elena National Cancer Institute, 00158, Rome, Italy. gdorazi@unich.it.
authors: Gabriella
authors: G
authors: D'Orazi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D045325:HCT116 Cells; D006801:Humans; D008819:Mice, Nude; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D017967:Zinc Compounds / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002712:Chlorides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D017967:Zinc Compounds; D004317:Doxorubicin; C016837:zinc chloride