title: β-Cryptoxanthin Synergistically Enhances the Antitumoral Activity of Oxaliplatin through ΔNP73 Negative Regulation in Colon Cancer.
abstract: BACKGROUND
  The acquired resistance to chemotherapy represents the major limitation in the treatment of cancer. New strategies to solve this failure and improve patients' outcomes are necessary. The cancer preventive effect of β-cryptoxanthin has been widely described in population studies. Few reports support its putative use as an antitumoral compound. Here we focus on the therapeutic potential of β-cryptoxanthin individually or in combination with oxaliplatin in colon cancer and try to decipher the molecular basis underlying its effect.
  
  
  METHODS
  Apoptosis, viability and proliferation assays, mouse models, and an intervention study in 20 healthy subjects were performed. A PCR array was carried out to unravel the molecular putative basis of the β-cryptoxanthin effect, and further signaling experiments were conducted. Comet Assay was completed to evaluate the genotoxicity of the treatments.
  
  
  RESULTS
  β-Cryptoxanthin differentially regulates the expression of the P73 variants in vitro, in vivo, and in a human intervention study. This carotenoid decreases the proliferation of cancer cells and cooperates with oxaliplatin to induce apoptosis through the negative regulation of ΔNP73. The antitumoral concentrations of oxaliplatin decrease in the presence of β-cryptoxanthin to achieve same percentage of growth inhibition. The genotoxicity in peripheral blood mononuclear cells of mice decreased in the combined treatment.
  
  
  CONCLUSIONS
  We propose a putative novel therapeutic strategy for the treatment of colon cancer based on the combination of β-cryptoxanthin and oxaliplatin. The combined regimen produced more benefit than either individual modality without increasing side effects. In addition, the concentration-limiting toxicity of oxaliplatin is reduced in the presence of the carotenoid.
authors.affiliation: Departamento de Medicina, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain.
authors.forename: Coral
authors.initials: C
authors.lastname: San Millán
authors.affiliation: Departamento de Medicina, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Soldevilla
authors.affiliation: Servicio de Anatomía Patológica, Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín
authors.affiliation: Grupo de señalización celular en cáncer, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gil-Calderón
authors.affiliation: Unidad de inmunología molecular, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Compte
authors.affiliation: Unidad de Vitaminas, Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez-Sacristán
authors.affiliation: Servicio de Bioquímica Clínica, Madrid, Spain.
authors.forename: Encarnación
authors.initials: E
authors.lastname: Donoso
authors.affiliation: Grupo de señalización celular en cáncer, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Peña
authors.affiliation: Servicio de Oncología radioterápica, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Romero
authors.affiliation: Unidad de Vitaminas, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Granado-Lorencio
authors.affiliation: Centro de Estudios Biosanitarios, Madrid, Spain. gemma.dominguez@uam.es felixbonillavelasco@gmail.com.
authors.forename: Félix
authors.initials: F
authors.lastname: Bonilla
authors.affiliation: Departamento de Medicina, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain. gemma.dominguez@uam.es felixbonillavelasco@gmail.com.
authors.forename: Gemma
authors.initials: G
authors.lastname: Domínguez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D065366:Cryptoxanthins / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D020033:Protein Isoforms; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D065366:Cryptoxanthins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D020033:Protein Isoforms; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D000077150:Oxaliplatin