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The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma

Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic inde...

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Autores principales: Grillone, Katia, Riillo, Caterina, Rocca, Roberta, Ascrizzi, Serena, Spanò, Virginia, Scionti, Francesca, Polerà, Nicoletta, Maruca, Annalisa, Barreca, Marilia, Juli, Giada, Arbitrio, Mariamena, Di Martino, Maria Teresa, Caracciolo, Daniele, Tagliaferri, Pierosandro, Alcaro, Stefano, Montalbano, Alessandra, Barraja, Paola, Tassone, Pierfrancesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499408/
https://www.ncbi.nlm.nih.gov/pubmed/36142133
http://dx.doi.org/10.3390/ijms231810222
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author Grillone, Katia
Riillo, Caterina
Rocca, Roberta
Ascrizzi, Serena
Spanò, Virginia
Scionti, Francesca
Polerà, Nicoletta
Maruca, Annalisa
Barreca, Marilia
Juli, Giada
Arbitrio, Mariamena
Di Martino, Maria Teresa
Caracciolo, Daniele
Tagliaferri, Pierosandro
Alcaro, Stefano
Montalbano, Alessandra
Barraja, Paola
Tassone, Pierfrancesco
author_facet Grillone, Katia
Riillo, Caterina
Rocca, Roberta
Ascrizzi, Serena
Spanò, Virginia
Scionti, Francesca
Polerà, Nicoletta
Maruca, Annalisa
Barreca, Marilia
Juli, Giada
Arbitrio, Mariamena
Di Martino, Maria Teresa
Caracciolo, Daniele
Tagliaferri, Pierosandro
Alcaro, Stefano
Montalbano, Alessandra
Barraja, Paola
Tassone, Pierfrancesco
author_sort Grillone, Katia
collection PubMed
description Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1/GADD34 complex. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. We found that the treatment with SIX2G inhibited cell viability by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2α protein level. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent.
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spelling pubmed-94994082022-09-23 The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma Grillone, Katia Riillo, Caterina Rocca, Roberta Ascrizzi, Serena Spanò, Virginia Scionti, Francesca Polerà, Nicoletta Maruca, Annalisa Barreca, Marilia Juli, Giada Arbitrio, Mariamena Di Martino, Maria Teresa Caracciolo, Daniele Tagliaferri, Pierosandro Alcaro, Stefano Montalbano, Alessandra Barraja, Paola Tassone, Pierfrancesco Int J Mol Sci Article Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1/GADD34 complex. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. We found that the treatment with SIX2G inhibited cell viability by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2α protein level. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent. MDPI 2022-09-06 /pmc/articles/PMC9499408/ /pubmed/36142133 http://dx.doi.org/10.3390/ijms231810222 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Grillone, Katia
Riillo, Caterina
Rocca, Roberta
Ascrizzi, Serena
Spanò, Virginia
Scionti, Francesca
Polerà, Nicoletta
Maruca, Annalisa
Barreca, Marilia
Juli, Giada
Arbitrio, Mariamena
Di Martino, Maria Teresa
Caracciolo, Daniele
Tagliaferri, Pierosandro
Alcaro, Stefano
Montalbano, Alessandra
Barraja, Paola
Tassone, Pierfrancesco
The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma
title The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma
title_full The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma
title_fullStr The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma
title_full_unstemmed The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma
title_short The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma
title_sort new microtubule-targeting agent six2g induces immunogenic cell death in multiple myeloma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499408/
https://www.ncbi.nlm.nih.gov/pubmed/36142133
http://dx.doi.org/10.3390/ijms231810222
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