PH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity

Angelo De Milito, Rossella Canese, Maria Lucia Marino, Martina Borghi, Manuela Iero, Antonello Villa, Giulietta Venturi, Francesco Lozupone, Elisabetta Iessi, Mariantonia Logozzi, Pamela Della Mina, Mario Santinami, Monica Rodolfo, Franca Podo, Licia Rivoltini, Stefano Fais

Research output: Contribution to journalArticle

157 Citations (Scopus)

Abstract

Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg-1) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients.

Original languageEnglish
Pages (from-to)207-219
Number of pages13
JournalInternational Journal of Cancer
Volume127
Issue number1
DOIs
Publication statusPublished - Jul 1 2010

Fingerprint

Esomeprazole
Proton Pump Inhibitors
Melanoma
Neoplasms
SCID Mice
Proton-Motive Force
Cell Death
Caspases
Cell Line
Caspase Inhibitors
Foster Home Care
Tumor Microenvironment
Prodrugs
Growth
Acidosis
Antineoplastic Agents
Protons
Magnetic Resonance Spectroscopy
Therapeutics
Cell Proliferation

Keywords

  • Human melanoma
  • Magnetic resonance spectroscopy
  • Proton pump inhibitors
  • SCID mice
  • Tumor acidity
  • Vacuolar ATPase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

PH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. / De Milito, Angelo; Canese, Rossella; Marino, Maria Lucia; Borghi, Martina; Iero, Manuela; Villa, Antonello; Venturi, Giulietta; Lozupone, Francesco; Iessi, Elisabetta; Logozzi, Mariantonia; Mina, Pamela Della; Santinami, Mario; Rodolfo, Monica; Podo, Franca; Rivoltini, Licia; Fais, Stefano.

In: International Journal of Cancer, Vol. 127, No. 1, 01.07.2010, p. 207-219.

Research output: Contribution to journalArticle

De Milito, A, Canese, R, Marino, ML, Borghi, M, Iero, M, Villa, A, Venturi, G, Lozupone, F, Iessi, E, Logozzi, M, Mina, PD, Santinami, M, Rodolfo, M, Podo, F, Rivoltini, L & Fais, S 2010, 'PH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity', International Journal of Cancer, vol. 127, no. 1, pp. 207-219. https://doi.org/10.1002/ijc.25009
De Milito, Angelo ; Canese, Rossella ; Marino, Maria Lucia ; Borghi, Martina ; Iero, Manuela ; Villa, Antonello ; Venturi, Giulietta ; Lozupone, Francesco ; Iessi, Elisabetta ; Logozzi, Mariantonia ; Mina, Pamela Della ; Santinami, Mario ; Rodolfo, Monica ; Podo, Franca ; Rivoltini, Licia ; Fais, Stefano. / PH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. In: International Journal of Cancer. 2010 ; Vol. 127, No. 1. pp. 207-219.
@article{f8fcc9698105472d8b35855ad2d625a0,
title = "PH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity",
abstract = "Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg-1) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients.",
keywords = "Human melanoma, Magnetic resonance spectroscopy, Proton pump inhibitors, SCID mice, Tumor acidity, Vacuolar ATPase",
author = "{De Milito}, Angelo and Rossella Canese and Marino, {Maria Lucia} and Martina Borghi and Manuela Iero and Antonello Villa and Giulietta Venturi and Francesco Lozupone and Elisabetta Iessi and Mariantonia Logozzi and Mina, {Pamela Della} and Mario Santinami and Monica Rodolfo and Franca Podo and Licia Rivoltini and Stefano Fais",
year = "2010",
month = "7",
day = "1",
doi = "10.1002/ijc.25009",
language = "English",
volume = "127",
pages = "207--219",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - PH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity

AU - De Milito, Angelo

AU - Canese, Rossella

AU - Marino, Maria Lucia

AU - Borghi, Martina

AU - Iero, Manuela

AU - Villa, Antonello

AU - Venturi, Giulietta

AU - Lozupone, Francesco

AU - Iessi, Elisabetta

AU - Logozzi, Mariantonia

AU - Mina, Pamela Della

AU - Santinami, Mario

AU - Rodolfo, Monica

AU - Podo, Franca

AU - Rivoltini, Licia

AU - Fais, Stefano

PY - 2010/7/1

Y1 - 2010/7/1

N2 - Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg-1) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients.

AB - Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg-1) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients.

KW - Human melanoma

KW - Magnetic resonance spectroscopy

KW - Proton pump inhibitors

KW - SCID mice

KW - Tumor acidity

KW - Vacuolar ATPase

UR - http://www.scopus.com/inward/record.url?scp=77953463274&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953463274&partnerID=8YFLogxK

U2 - 10.1002/ijc.25009

DO - 10.1002/ijc.25009

M3 - Article

C2 - 19876915

AN - SCOPUS:77953463274

VL - 127

SP - 207

EP - 219

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 1

ER -