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Effect of Lipoic Acid on the Biochemical Mechanisms of Resistance to Bortezomib in SH-SY5Y Neuroblastoma Cells

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Abstract

Neuroblastoma (NB) is an extracranial solid cancer and the most common cancer in infancy. Despite the standard treatment for NB is based on the combination of chemotherapeutic drugs such as doxorubicin, vincristine, cyclophosphamide, and cisplatin, chemoresistance occurs over the time. The aim of the present research was to evaluate the effect of bortezomib (BTZ) (50 nM) on NB cell viability and how lipoic acid (ALA) (100 μM) modifies pharmacological response to this chemotherapeutic agent. Cell viability was assessed by ATP luminescence assay whereas expression of oxidative stress marker (i.e., heme oxygenase-1) and endoplasmic reticulum stress proteins was performed by real-time PCR, western blot, and immunofluorescence. Our data showed that BTZ treatment significantly reduced cell viability when compared to untreated cultures (about 40%). Interestingly, ALA significantly reduced the efficacy of BTZ (about 30%). Furthermore, BTZ significantly induced heme oxygenase-1 as a result of increased oxidative stress and such overexpression was prevented by concomitant treatment with ALA. Similarly, ALA significantly reduced BTZ-mediated endoplasmic reticulum stress as measured by reduction in BiP1 and IRE1α, ERO1α, and PDI expression. In conclusion, our data suggest that BTZ efficacy is dependent on cellular redox status and such mechanisms may be responsible of chemoresistance to this chemotherapeutic agent.

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Author notes

  1. Roberto Avola and Vincenzo Bramanti contributed equally

Authors and Affiliations

  1. Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 87, 95100, Catania, Italy

    Daniele Tibullo, Cesarina Giallongo, Giuseppina Camiolo, Martina Cristaldi, Maria Violetta Brundo, Carmelina Daniela Anfuso, Gabriella Lupo, Giovanni Li Volti, Roberto Avola & Vincenzo Bramanti

  2. Division of Haematology, A.O.U. “Policlinico–Vittorio Emanuele”, University of Catania, Via Citelli 6, 95100, Catania, Italy

    Daniele Tibullo, Cesarina Giallongo & Fabrizio Puglisi

  3. School of Bioscience and Veterinary Medicine, University of Camerino, via Gentile III da Varano, Camerino, 62032, Italy

    Daniele Tomassoni

  4. Division of Microbiology and Virology, Villa Sofia Hospital, A.O.O.R. “Villa Sofia–Cervello”, Piazza Salerno 1, 90146, Palermo, Italy

    Tomaso Stampone & Vincenzo Bramanti

  5. School of Medicinal Sciences and Health Products, University of Camerino, via Madonna delle Carceri 9, Camerino, 62032, Italy

    Francesco Amenta

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  1. Daniele Tibullo
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  2. Cesarina Giallongo
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Correspondence to Roberto Avola.

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Tibullo, D., Giallongo, C., Puglisi, F. et al. Effect of Lipoic Acid on the Biochemical Mechanisms of Resistance to Bortezomib in SH-SY5Y Neuroblastoma Cells. Mol Neurobiol 55, 3344–3350 (2018). https://doi.org/10.1007/s12035-017-0575-6

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