Restoring microenvironmental redox and pH homeostasis inhibits neoplastic cell growth and migration: therapeutic efficacy of esomeprazole plus sulfasalazine on 3-MCA-induced sarcoma

Enrica Balza, Patrizia Castellani, Paola Sanchez Moreno, Patrizia Piccioli, Iria Medraño-Fernandez, Claudia Semino, Anna Rubartelli

Research output: Contribution to journalArticle

Abstract

Neoplastic cells live in a stressful context and survive thanks to their ability to overcome stress. Thus, tumor cell responses to stress are potential therapeutic targets. We selected two such responses in melanoma and sarcoma cells: the xc- antioxidant system, that opposes oxidative stress, and surface v-ATPases that counteract the low pHi by extruding protons, and targeted them with the xc- blocker sulfasalazine and the proton pump inhibitor esomeprazole. Sulfasalazine inhibited the cystine/cysteine redox cycle and esomeprazole decreased pHi while increasing pHe in tumor cell lines. Although the single treatment with either drug slightly inhibited cell proliferation and motility, the association of sulfasalazine and esomeprazole powerfully decreased sarcoma and melanoma growth and migration. In the 3-methylcholanthrene (3-MCA)-induced sarcoma model, the combined therapy strongly reduced the tumor burden and increased the survival time: notably, 22 % of double-treated mice recovered and survived off therapy. Tumor-associated macrophages (TAM) displaying M2 markers, that abundantly infiltrate sarcoma and melanoma, overexpress xc- and membrane v-ATPases and were drastically decreased in tumors from mice undergone the combined therapy. Thus, the double targeting of tumor cells and macrophages by sulfasalazine and esomeprazole has a double therapeutic effect, as decreasing TAM infiltration deprives tumor cells of a crucial allied. Sulfasalazine and esomeprazole may therefore display unexpected therapeutic values, especially in case of hard-to-treat cancers.

Original languageEnglish
Pages (from-to)67482-67496
Number of pages15
JournalOncotarget
Volume8
Issue number40
DOIs
Publication statusPublished - Sep 15 2017

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Esomeprazole
Sulfasalazine
Methylcholanthrene
Sarcoma
Oxidation-Reduction
Cell Movement
Homeostasis
Growth
Neoplasms
Melanoma
Macrophages
Therapeutics
Adenosine Triphosphatases
Cystine
Proton Pump Inhibitors
Therapeutic Uses
Tumor Burden
Tumor Cell Line
Cysteine
Protons

Keywords

  • Journal Article

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Restoring microenvironmental redox and pH homeostasis inhibits neoplastic cell growth and migration : therapeutic efficacy of esomeprazole plus sulfasalazine on 3-MCA-induced sarcoma. / Balza, Enrica; Castellani, Patrizia; Moreno, Paola Sanchez; Piccioli, Patrizia; Medraño-Fernandez, Iria; Semino, Claudia; Rubartelli, Anna.

In: Oncotarget, Vol. 8, No. 40, 15.09.2017, p. 67482-67496.

Research output: Contribution to journalArticle

Balza, Enrica ; Castellani, Patrizia ; Moreno, Paola Sanchez ; Piccioli, Patrizia ; Medraño-Fernandez, Iria ; Semino, Claudia ; Rubartelli, Anna. / Restoring microenvironmental redox and pH homeostasis inhibits neoplastic cell growth and migration : therapeutic efficacy of esomeprazole plus sulfasalazine on 3-MCA-induced sarcoma. In: Oncotarget. 2017 ; Vol. 8, No. 40. pp. 67482-67496.
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AB - Neoplastic cells live in a stressful context and survive thanks to their ability to overcome stress. Thus, tumor cell responses to stress are potential therapeutic targets. We selected two such responses in melanoma and sarcoma cells: the xc- antioxidant system, that opposes oxidative stress, and surface v-ATPases that counteract the low pHi by extruding protons, and targeted them with the xc- blocker sulfasalazine and the proton pump inhibitor esomeprazole. Sulfasalazine inhibited the cystine/cysteine redox cycle and esomeprazole decreased pHi while increasing pHe in tumor cell lines. Although the single treatment with either drug slightly inhibited cell proliferation and motility, the association of sulfasalazine and esomeprazole powerfully decreased sarcoma and melanoma growth and migration. In the 3-methylcholanthrene (3-MCA)-induced sarcoma model, the combined therapy strongly reduced the tumor burden and increased the survival time: notably, 22 % of double-treated mice recovered and survived off therapy. Tumor-associated macrophages (TAM) displaying M2 markers, that abundantly infiltrate sarcoma and melanoma, overexpress xc- and membrane v-ATPases and were drastically decreased in tumors from mice undergone the combined therapy. Thus, the double targeting of tumor cells and macrophages by sulfasalazine and esomeprazole has a double therapeutic effect, as decreasing TAM infiltration deprives tumor cells of a crucial allied. Sulfasalazine and esomeprazole may therefore display unexpected therapeutic values, especially in case of hard-to-treat cancers.

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