title: Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients' bed.
abstract: BACKGROUND
  Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H +-rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma.
  
  
  METHODS
  MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin.
  
  
  RESULTS
  Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients.
  
  
  CONCLUSIONS
  This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.forename: Francesca
authors.initials: F
authors.lastname: Perut
authors.forename: Franca
authors.initials: F
authors.lastname: Fagioli
authors.forename: Adalberto
authors.initials: A
authors.lastname: Brach Del Prever
authors.forename: Cristina
authors.initials: C
authors.lastname: Meazza
authors.forename: Antonina
authors.initials: A
authors.lastname: Parafioriti
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Marco
authors.initials: M
authors.lastname: Gambarotti
authors.forename: Sofia
authors.initials: S
authors.lastname: Avnet
authors.forename: Nicola
authors.initials: N
authors.lastname: Baldini
authors.affiliation: Anti-Tumour Drugs Section Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy. stefano.fais@iss.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
mesh_terms: D000293:Adolescent; D000328:Adult; D045744:Cell Line, Tumor; D002648:Child; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D054328:Proton Pump Inhibitors / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D054328:Proton Pump Inhibitors