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Heme Oxygenase Inhibition Sensitizes Neuroblastoma Cells to Carfilzomib

  • Ignazio Barbagallo
  • Cesarina Giallongo
  • Giovanni Li Volti
  • Alfio Distefano
  • Giuseppina Camiolo
  • Marco Raffaele
  • Loredana Salerno
  • Valeria Pittalà
  • Valeria Sorrenti
  • Roberto Avola
  • Michelino Di Rosa
  • Luca Vanella
  • Francesco Di Raimondo
  • Daniele Tibullo
Article

Abstract

Neuroblastoma (NB) is an embryonic malignancy affecting the physiological development of adrenal medulla and paravertebral sympathetic ganglia in early infancy. Proteasome inhibitors (PIs) (i.e., carfilzomib (CFZ)) may represent a possible pharmacological treatment for solid tumors including NB. In the present study, we tested the effect of a novel non-competitive inhibitor of heme oxygenase-1 (HO-1), LS1/71, as a possible adjuvant therapy for the efficacy of CFZ in neuroblastoma cells. Our results showed that CFZ increased both HO-1 gene expression (about 18-fold) and HO activity (about 8-fold), following activation of the ER stress pathway. The involvement of HO-1 in CFZ-mediated cytotoxicity was further confirmed by the protective effect of pharmacological induction of HO-1, significantly attenuating cytotoxicity. In addition, HO-1 selective inhibition by a specific siRNA increased the cytotoxic effect following CFZ treatment in NB whereas SnMP, a competitive pharmacological inhibitor of HO, showed no changes in cytotoxicity. Our data suggest that treatment with CFZ produces ER stress in NB without activation of CHOP-mediated apoptosis, whereas co-treatment with CFZ and LS1/71 led to apoptosis activation and CHOP expression induction. In conclusion, our study showed that treatment with the non-competitive inhibitor of HO-1, LS1 / 71, increased cytotoxicity mediated by CFZ, triggering apoptosis following ER stress activation. These results suggest that PIs may represent a possible pharmacological treatment for solid tumors and that HO-1 inhibition may represent a possible strategy to overcome chemoresistance and increase the efficacy of chemotherapic regimens.

Keywords

Heme oxygenase Inhibitors Proteasome Neuroblastoma Carfilzomib 

Notes

Acknowledgments

This work was financially supported by Fir 2017 from the University of Catania (PI: Loredana Salerno).

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ignazio Barbagallo
    • 1
  • Cesarina Giallongo
    • 2
  • Giovanni Li Volti
    • 2
  • Alfio Distefano
    • 2
  • Giuseppina Camiolo
    • 2
  • Marco Raffaele
    • 1
  • Loredana Salerno
    • 1
  • Valeria Pittalà
    • 1
  • Valeria Sorrenti
    • 1
  • Roberto Avola
    • 2
  • Michelino Di Rosa
    • 2
  • Luca Vanella
    • 1
  • Francesco Di Raimondo
    • 3
  • Daniele Tibullo
    • 2
  1. 1.Department of Drug Science, Biochemistry SectionUniversity of CataniaCataniaItaly
  2. 2.Department of Biomedical and Biotechnological SciencesUniversity of CataniaCataniaItaly
  3. 3.Department of Surgery, Medical and Surgical SpecialtiesUniversity of CataniaCataniaItaly

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