Proton pump inhibitor chemosensitization in human osteosarcoma

From the bench to the patients' bed

Stefano Ferrari, Francesca Perut, Franca Fagioli, Adalberto Brach Del Prever, Cristina Meazza, Antonina Parafioriti, Piero Picci, Marco Gambarotti, Sofia Avnet, Nicola Baldini, Stefano Fais

Research output: Contribution to journalArticle

58 Citations (Scopus)

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.Method: 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.Conclusion: This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy.

Original languageEnglish
Article number268
JournalJournal of Translational Medicine
Volume11
Issue number1
DOIs
Publication statusPublished - Oct 24 2013

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Hospital beds
Proton Pump Inhibitors
Osteosarcoma
Tumors
Cisplatin
Chemotherapy
Neoplasms
Cells
Heterografts
Drug Therapy
Toxicity
Erythrosine
Esomeprazole
Pharmaceutical Preparations
Cell Line
Oncology
Protonation
Cell proliferation
Methotrexate
Doxorubicin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Proton pump inhibitor chemosensitization in human osteosarcoma : From the bench to the patients' bed. / Ferrari, Stefano; Perut, Francesca; Fagioli, Franca; Brach Del Prever, Adalberto; Meazza, Cristina; Parafioriti, Antonina; Picci, Piero; Gambarotti, Marco; Avnet, Sofia; Baldini, Nicola; Fais, Stefano.

In: Journal of Translational Medicine, Vol. 11, No. 1, 268, 24.10.2013.

Research output: Contribution to journalArticle

Ferrari, Stefano ; Perut, Francesca ; Fagioli, Franca ; Brach Del Prever, Adalberto ; Meazza, Cristina ; Parafioriti, Antonina ; Picci, Piero ; Gambarotti, Marco ; Avnet, Sofia ; Baldini, Nicola ; Fais, Stefano. / Proton pump inhibitor chemosensitization in human osteosarcoma : From the bench to the patients' bed. In: Journal of Translational Medicine. 2013 ; Vol. 11, No. 1.
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AU - Brach Del Prever, Adalberto

AU - Meazza, Cristina

AU - Parafioriti, Antonina

AU - Picci, Piero

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AU - Baldini, Nicola

AU - Fais, Stefano

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