Cargando…

Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models

Breast cancer is the most frequent cancer in women. Despite recent clinical advances, new therapeutic approaches are still required. The cystine-glutamate antiporter xCT, encoded by the SLC7A11 gene, which imports cystine in exchange with glutamate, is a potentially new target for breast cancer ther...

Descripción completa

Detalles Bibliográficos
Autores principales: Barutello, Giuseppina, Di Lorenzo, Antonino, Gasparetto, Alessandro, Galiazzi, Chiara, Bolli, Elisabetta, Conti, Laura, Cavallo, Federica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688020/
https://www.ncbi.nlm.nih.gov/pubmed/36359363
http://dx.doi.org/10.3390/biomedicines10112843
_version_ 1784836161077772288
author Barutello, Giuseppina
Di Lorenzo, Antonino
Gasparetto, Alessandro
Galiazzi, Chiara
Bolli, Elisabetta
Conti, Laura
Cavallo, Federica
author_facet Barutello, Giuseppina
Di Lorenzo, Antonino
Gasparetto, Alessandro
Galiazzi, Chiara
Bolli, Elisabetta
Conti, Laura
Cavallo, Federica
author_sort Barutello, Giuseppina
collection PubMed
description Breast cancer is the most frequent cancer in women. Despite recent clinical advances, new therapeutic approaches are still required. The cystine-glutamate antiporter xCT, encoded by the SLC7A11 gene, which imports cystine in exchange with glutamate, is a potentially new target for breast cancer therapy, being involved in tumor cell redox balance and resistance to therapies. xCT expression is regulated by the oncosuppressor p53, which is mutated in many breast cancers. Indeed, mutant p53 (mut-p53) can induce xCT post-transcriptional down modulation, rendering mut-p53 tumors susceptible to oxidative damage. Interestingly, the drug APR-246, developed to restore the wild-type function of p53 in tumors harboring its mutation, alters the cell redox balance in a p53-independent way, possibly rendering the cells more sensitive to xCT inhibition. Here, we propose a combinatorial treatment based on xCT immunetargeting and APR-246 treatment as a strategy for tackling breast cancer. We demonstrate that combining the inhibition of xCT with the APR-246 drug significantly decreased breast cancer cell viability in vitro and induced apoptosis and affected cancer stem cells’ self-renewal compared to the single treatments. Moreover, the immunetargeting of xCT through DNA vaccination in combination with APR-246 treatment synergistically hinders tumor progression and prevents lung metastasis formation in vivo. These effects can be mediated by the production of anti-xCT antibodies that are able to induce the antibody dependent cellular cytotoxicity of tumor cells. Overall, we demonstrate that DNA vaccination against xCT can synergize with APR-246 treatment and enhance its therapeutic effect. Thus, APR-246 treatment in combination with xCT immunetargeting may open new perspectives in the management of breast cancer.
format Online
Article
Text
id pubmed-9688020
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96880202022-11-25 Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models Barutello, Giuseppina Di Lorenzo, Antonino Gasparetto, Alessandro Galiazzi, Chiara Bolli, Elisabetta Conti, Laura Cavallo, Federica Biomedicines Article Breast cancer is the most frequent cancer in women. Despite recent clinical advances, new therapeutic approaches are still required. The cystine-glutamate antiporter xCT, encoded by the SLC7A11 gene, which imports cystine in exchange with glutamate, is a potentially new target for breast cancer therapy, being involved in tumor cell redox balance and resistance to therapies. xCT expression is regulated by the oncosuppressor p53, which is mutated in many breast cancers. Indeed, mutant p53 (mut-p53) can induce xCT post-transcriptional down modulation, rendering mut-p53 tumors susceptible to oxidative damage. Interestingly, the drug APR-246, developed to restore the wild-type function of p53 in tumors harboring its mutation, alters the cell redox balance in a p53-independent way, possibly rendering the cells more sensitive to xCT inhibition. Here, we propose a combinatorial treatment based on xCT immunetargeting and APR-246 treatment as a strategy for tackling breast cancer. We demonstrate that combining the inhibition of xCT with the APR-246 drug significantly decreased breast cancer cell viability in vitro and induced apoptosis and affected cancer stem cells’ self-renewal compared to the single treatments. Moreover, the immunetargeting of xCT through DNA vaccination in combination with APR-246 treatment synergistically hinders tumor progression and prevents lung metastasis formation in vivo. These effects can be mediated by the production of anti-xCT antibodies that are able to induce the antibody dependent cellular cytotoxicity of tumor cells. Overall, we demonstrate that DNA vaccination against xCT can synergize with APR-246 treatment and enhance its therapeutic effect. Thus, APR-246 treatment in combination with xCT immunetargeting may open new perspectives in the management of breast cancer. MDPI 2022-11-08 /pmc/articles/PMC9688020/ /pubmed/36359363 http://dx.doi.org/10.3390/biomedicines10112843 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
Barutello, Giuseppina
Di Lorenzo, Antonino
Gasparetto, Alessandro
Galiazzi, Chiara
Bolli, Elisabetta
Conti, Laura
Cavallo, Federica
Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models
title Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models
title_full Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models
title_fullStr Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models
title_full_unstemmed Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models
title_short Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models
title_sort immunotherapy against the cystine/glutamate antiporter xct improves the efficacy of apr-246 in preclinical breast cancer models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688020/
https://www.ncbi.nlm.nih.gov/pubmed/36359363
http://dx.doi.org/10.3390/biomedicines10112843
work_keys_str_mv AT barutellogiuseppina immunotherapyagainstthecystineglutamateantiporterxctimprovestheefficacyofapr246inpreclinicalbreastcancermodels
AT dilorenzoantonino immunotherapyagainstthecystineglutamateantiporterxctimprovestheefficacyofapr246inpreclinicalbreastcancermodels
AT gasparettoalessandro immunotherapyagainstthecystineglutamateantiporterxctimprovestheefficacyofapr246inpreclinicalbreastcancermodels
AT galiazzichiara immunotherapyagainstthecystineglutamateantiporterxctimprovestheefficacyofapr246inpreclinicalbreastcancermodels
AT bollielisabetta immunotherapyagainstthecystineglutamateantiporterxctimprovestheefficacyofapr246inpreclinicalbreastcancermodels
AT contilaura immunotherapyagainstthecystineglutamateantiporterxctimprovestheefficacyofapr246inpreclinicalbreastcancermodels
AT cavallofederica immunotherapyagainstthecystineglutamateantiporterxctimprovestheefficacyofapr246inpreclinicalbreastcancermodels