Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models

Autores
Sobol, Natasha Tatiana; Solernó, Luisina María; Llavona, Candela; Alonso, Daniel Fernando; Garona, Juan
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: Colorectal cancer (CRC) is a leading cause of cancerassociated mortality worldwide. Despite being an essential component of systemic chemotherapy for advanced CRC, 5-fluorouracil (5-FU) clinical use has severe limitations, such as high toxicity, low selectivity and drug resistance. [V4Q5]dDAVP (1-deamino-4-valine-5-glutamine- 8-D-arginine vasopressin) is a peptide vasopressin analog and a selective agonist of the arginine vasopressin type 2 membrane receptor (AVPR2), expressed in microvascular and tumor tissue. This synthetic compound has well-proven antitumor and antimetastatic activity in different tumor types, including metastatic CRC. The objective of this work was to assess the potential combinational benefits in preclinical CRC models after [V4Q5]dDAVP addition to 5-FU. Methods: Effects on cellular viability, cell cycle progression, apoptosis and molecular mechanisms associated to [V4Q5]dDAVP treatment in combination with 5-FU were evaluated in murine CT-26 and human COLO-205 cell lines. In vivo, impact of dual therapy was explored on CRC tumor growth and metastatic spread. Results: In CRC cells, [V4Q5]dDAVP (1 μM) addition to sub-IC50 5-FU concentrations resulted in the enhancement of cytostatic effects induced by chemotherapy. Reduction of cell viability after combined treatment was associated with cell cycle arrest in the G0/G1 phase, induction of apoptosis and increased gene expression of the cyclindependent kinase inhibitor p21 (CDKN1A) and the tumor suppressor p53 (TP53) in malignant cells, as assessed by flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), and quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. In vivo, intravenous administration of [V4Q5]dDAVP (0.3 μg/kg) in combination with safe low doses of 5-FU (50 or 80 mg/kg for CT-26 or COLO-205 tumor models, respectively) effectively abrogated CRC growth, reducing aggressiveness of primary lesions and increasing survival of tumor-bearing mice. In addition, concomitant administration of [V4Q5]dDAVP and 5-FU inhibited pulmonary metastasis formation by CT-26 cells in immunocompetent mice, especially reducing macrometastatic disease. Conclusions: [V4Q5]dDAVP seems to enhance the efficacy of 5-FUbased chemotherapy in CRC by modulating tumor progression, as well as metastatic dissemination, suggesting its potential role as a safe and cost-effective co-adjuvant agent for the management of advanced CRC.
Fil: Sobol, Natasha Tatiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
Fil: Solernó, Luisina María. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
Fil: Llavona, Candela. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
Fil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
Fil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
Materia
5-FU
ANTIMETASTATIC
AVPR2
CO-ADJUVANT THERAPY
COLORECTAL CANCER
[V4Q5]DDAVP
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/222809
Acceder
id CONICETDig_346d57782344242fd94d8856cd99176f
oai_identifier_str oai:ri.conicet.gov.ar:11336/222809
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer ModelsSobol, Natasha TatianaSolernó, Luisina MaríaLlavona, CandelaAlonso, Daniel FernandoGarona, Juan5-FUANTIMETASTATICAVPR2CO-ADJUVANT THERAPYCOLORECTAL CANCER[V4Q5]DDAVPhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Background: Colorectal cancer (CRC) is a leading cause of cancerassociated mortality worldwide. Despite being an essential component of systemic chemotherapy for advanced CRC, 5-fluorouracil (5-FU) clinical use has severe limitations, such as high toxicity, low selectivity and drug resistance. [V4Q5]dDAVP (1-deamino-4-valine-5-glutamine- 8-D-arginine vasopressin) is a peptide vasopressin analog and a selective agonist of the arginine vasopressin type 2 membrane receptor (AVPR2), expressed in microvascular and tumor tissue. This synthetic compound has well-proven antitumor and antimetastatic activity in different tumor types, including metastatic CRC. The objective of this work was to assess the potential combinational benefits in preclinical CRC models after [V4Q5]dDAVP addition to 5-FU. Methods: Effects on cellular viability, cell cycle progression, apoptosis and molecular mechanisms associated to [V4Q5]dDAVP treatment in combination with 5-FU were evaluated in murine CT-26 and human COLO-205 cell lines. In vivo, impact of dual therapy was explored on CRC tumor growth and metastatic spread. Results: In CRC cells, [V4Q5]dDAVP (1 μM) addition to sub-IC50 5-FU concentrations resulted in the enhancement of cytostatic effects induced by chemotherapy. Reduction of cell viability after combined treatment was associated with cell cycle arrest in the G0/G1 phase, induction of apoptosis and increased gene expression of the cyclindependent kinase inhibitor p21 (CDKN1A) and the tumor suppressor p53 (TP53) in malignant cells, as assessed by flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), and quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. In vivo, intravenous administration of [V4Q5]dDAVP (0.3 μg/kg) in combination with safe low doses of 5-FU (50 or 80 mg/kg for CT-26 or COLO-205 tumor models, respectively) effectively abrogated CRC growth, reducing aggressiveness of primary lesions and increasing survival of tumor-bearing mice. In addition, concomitant administration of [V4Q5]dDAVP and 5-FU inhibited pulmonary metastasis formation by CT-26 cells in immunocompetent mice, especially reducing macrometastatic disease. Conclusions: [V4Q5]dDAVP seems to enhance the efficacy of 5-FUbased chemotherapy in CRC by modulating tumor progression, as well as metastatic dissemination, suggesting its potential role as a safe and cost-effective co-adjuvant agent for the management of advanced CRC.Fil: Sobol, Natasha Tatiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; ArgentinaFil: Solernó, Luisina María. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; ArgentinaFil: Llavona, Candela. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; ArgentinaFil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; ArgentinaFil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; ArgentinaElmer Press2023-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/222809Sobol, Natasha Tatiana; Solernó, Luisina María; Llavona, Candela; Alonso, Daniel Fernando; Garona, Juan; Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models; Elmer Press; World Journal of Oncology; 14; 6; 12-2023; 540-5501920-45311920-454XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.wjon.org/index.php/WJON/article/view/1715info:eu-repo/semantics/altIdentifier/doi/10.14740/wjon1715info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:40:00Zoai:ri.conicet.gov.ar:11336/222809instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:40:00.605CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models
title Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models
spellingShingle Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models
Sobol, Natasha Tatiana
5-FU
ANTIMETASTATIC
AVPR2
CO-ADJUVANT THERAPY
COLORECTAL CANCER
[V4Q5]DDAVP
title_short Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models
title_full Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models
title_fullStr Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models
title_full_unstemmed Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models
title_sort Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models
dc.creator.none.fl_str_mv Sobol, Natasha Tatiana
Solernó, Luisina María
Llavona, Candela
Alonso, Daniel Fernando
Garona, Juan
author Sobol, Natasha Tatiana
author_facet Sobol, Natasha Tatiana
Solernó, Luisina María
Llavona, Candela
Alonso, Daniel Fernando
Garona, Juan
author_role author
author2 Solernó, Luisina María
Llavona, Candela
Alonso, Daniel Fernando
Garona, Juan
author2_role author
author
author
author
dc.subject.none.fl_str_mv 5-FU
ANTIMETASTATIC
AVPR2
CO-ADJUVANT THERAPY
COLORECTAL CANCER
[V4Q5]DDAVP
topic 5-FU
ANTIMETASTATIC
AVPR2
CO-ADJUVANT THERAPY
COLORECTAL CANCER
[V4Q5]DDAVP
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: Colorectal cancer (CRC) is a leading cause of cancerassociated mortality worldwide. Despite being an essential component of systemic chemotherapy for advanced CRC, 5-fluorouracil (5-FU) clinical use has severe limitations, such as high toxicity, low selectivity and drug resistance. [V4Q5]dDAVP (1-deamino-4-valine-5-glutamine- 8-D-arginine vasopressin) is a peptide vasopressin analog and a selective agonist of the arginine vasopressin type 2 membrane receptor (AVPR2), expressed in microvascular and tumor tissue. This synthetic compound has well-proven antitumor and antimetastatic activity in different tumor types, including metastatic CRC. The objective of this work was to assess the potential combinational benefits in preclinical CRC models after [V4Q5]dDAVP addition to 5-FU. Methods: Effects on cellular viability, cell cycle progression, apoptosis and molecular mechanisms associated to [V4Q5]dDAVP treatment in combination with 5-FU were evaluated in murine CT-26 and human COLO-205 cell lines. In vivo, impact of dual therapy was explored on CRC tumor growth and metastatic spread. Results: In CRC cells, [V4Q5]dDAVP (1 μM) addition to sub-IC50 5-FU concentrations resulted in the enhancement of cytostatic effects induced by chemotherapy. Reduction of cell viability after combined treatment was associated with cell cycle arrest in the G0/G1 phase, induction of apoptosis and increased gene expression of the cyclindependent kinase inhibitor p21 (CDKN1A) and the tumor suppressor p53 (TP53) in malignant cells, as assessed by flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), and quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. In vivo, intravenous administration of [V4Q5]dDAVP (0.3 μg/kg) in combination with safe low doses of 5-FU (50 or 80 mg/kg for CT-26 or COLO-205 tumor models, respectively) effectively abrogated CRC growth, reducing aggressiveness of primary lesions and increasing survival of tumor-bearing mice. In addition, concomitant administration of [V4Q5]dDAVP and 5-FU inhibited pulmonary metastasis formation by CT-26 cells in immunocompetent mice, especially reducing macrometastatic disease. Conclusions: [V4Q5]dDAVP seems to enhance the efficacy of 5-FUbased chemotherapy in CRC by modulating tumor progression, as well as metastatic dissemination, suggesting its potential role as a safe and cost-effective co-adjuvant agent for the management of advanced CRC.
Fil: Sobol, Natasha Tatiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
Fil: Solernó, Luisina María. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
Fil: Llavona, Candela. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
Fil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
Fil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Néstor Carlos Kirchner. Centro de Medicina Traslacional; Argentina
description Background: Colorectal cancer (CRC) is a leading cause of cancerassociated mortality worldwide. Despite being an essential component of systemic chemotherapy for advanced CRC, 5-fluorouracil (5-FU) clinical use has severe limitations, such as high toxicity, low selectivity and drug resistance. [V4Q5]dDAVP (1-deamino-4-valine-5-glutamine- 8-D-arginine vasopressin) is a peptide vasopressin analog and a selective agonist of the arginine vasopressin type 2 membrane receptor (AVPR2), expressed in microvascular and tumor tissue. This synthetic compound has well-proven antitumor and antimetastatic activity in different tumor types, including metastatic CRC. The objective of this work was to assess the potential combinational benefits in preclinical CRC models after [V4Q5]dDAVP addition to 5-FU. Methods: Effects on cellular viability, cell cycle progression, apoptosis and molecular mechanisms associated to [V4Q5]dDAVP treatment in combination with 5-FU were evaluated in murine CT-26 and human COLO-205 cell lines. In vivo, impact of dual therapy was explored on CRC tumor growth and metastatic spread. Results: In CRC cells, [V4Q5]dDAVP (1 μM) addition to sub-IC50 5-FU concentrations resulted in the enhancement of cytostatic effects induced by chemotherapy. Reduction of cell viability after combined treatment was associated with cell cycle arrest in the G0/G1 phase, induction of apoptosis and increased gene expression of the cyclindependent kinase inhibitor p21 (CDKN1A) and the tumor suppressor p53 (TP53) in malignant cells, as assessed by flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), and quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. In vivo, intravenous administration of [V4Q5]dDAVP (0.3 μg/kg) in combination with safe low doses of 5-FU (50 or 80 mg/kg for CT-26 or COLO-205 tumor models, respectively) effectively abrogated CRC growth, reducing aggressiveness of primary lesions and increasing survival of tumor-bearing mice. In addition, concomitant administration of [V4Q5]dDAVP and 5-FU inhibited pulmonary metastasis formation by CT-26 cells in immunocompetent mice, especially reducing macrometastatic disease. Conclusions: [V4Q5]dDAVP seems to enhance the efficacy of 5-FUbased chemotherapy in CRC by modulating tumor progression, as well as metastatic dissemination, suggesting its potential role as a safe and cost-effective co-adjuvant agent for the management of advanced CRC.
publishDate 2023
dc.date.none.fl_str_mv 2023-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/222809
Sobol, Natasha Tatiana; Solernó, Luisina María; Llavona, Candela; Alonso, Daniel Fernando; Garona, Juan; Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models; Elmer Press; World Journal of Oncology; 14; 6; 12-2023; 540-550
1920-4531
1920-454X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/222809
identifier_str_mv Sobol, Natasha Tatiana; Solernó, Luisina María; Llavona, Candela; Alonso, Daniel Fernando; Garona, Juan; Vasopressin Analog [V4Q5]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models; Elmer Press; World Journal of Oncology; 14; 6; 12-2023; 540-550
1920-4531
1920-454X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.wjon.org/index.php/WJON/article/view/1715
info:eu-repo/semantics/altIdentifier/doi/10.14740/wjon1715
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elmer Press
publisher.none.fl_str_mv Elmer Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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