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Vasopressin Analog [V(4)Q(5)]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-associated 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. [V(4...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elmer Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10681791/ https://www.ncbi.nlm.nih.gov/pubmed/38022396 http://dx.doi.org/10.14740/wjon1715 |
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author | Sobol, Natasha T. Solerno, Luisina M. Llavona, Candela Alonso, Daniel F. Garona, Juan |
author_facet | Sobol, Natasha T. Solerno, Luisina M. Llavona, Candela Alonso, Daniel F. Garona, Juan |
author_sort | Sobol, Natasha T. |
collection | PubMed |
description | BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-associated 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. [V(4)Q(5)]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 [V(4)Q(5)]dDAVP addition to 5-FU. METHODS: Effects on cellular viability, cell cycle progression, apoptosis and molecular mechanisms associated to [V(4)Q(5)]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, [V(4)Q(5)]dDAVP (1 µM) addition to sub-IC(50) 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 G(0)/G(1) phase, induction of apoptosis and increased gene expression of the cyclin-dependent 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 [V(4)Q(5)]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 [V(4)Q(5)]dDAVP and 5-FU inhibited pulmonary metastasis formation by CT-26 cells in immunocompetent mice, especially reducing macrometastatic disease. CONCLUSIONS: [V(4)Q(5)]dDAVP seems to enhance the efficacy of 5-FU-based 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. |
format | Online Article Text |
id | pubmed-10681791 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elmer Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-106817912023-11-18 Vasopressin Analog [V(4)Q(5)]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models Sobol, Natasha T. Solerno, Luisina M. Llavona, Candela Alonso, Daniel F. Garona, Juan World J Oncol Original Article BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-associated 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. [V(4)Q(5)]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 [V(4)Q(5)]dDAVP addition to 5-FU. METHODS: Effects on cellular viability, cell cycle progression, apoptosis and molecular mechanisms associated to [V(4)Q(5)]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, [V(4)Q(5)]dDAVP (1 µM) addition to sub-IC(50) 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 G(0)/G(1) phase, induction of apoptosis and increased gene expression of the cyclin-dependent 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 [V(4)Q(5)]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 [V(4)Q(5)]dDAVP and 5-FU inhibited pulmonary metastasis formation by CT-26 cells in immunocompetent mice, especially reducing macrometastatic disease. CONCLUSIONS: [V(4)Q(5)]dDAVP seems to enhance the efficacy of 5-FU-based 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. Elmer Press 2023-12 2023-11-18 /pmc/articles/PMC10681791/ /pubmed/38022396 http://dx.doi.org/10.14740/wjon1715 Text en Copyright 2023, Sobol et al. https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Sobol, Natasha T. Solerno, Luisina M. Llavona, Candela Alonso, Daniel F. Garona, Juan Vasopressin Analog [V(4)Q(5)]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models |
title | Vasopressin Analog [V(4)Q(5)]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models |
title_full | Vasopressin Analog [V(4)Q(5)]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models |
title_fullStr | Vasopressin Analog [V(4)Q(5)]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models |
title_full_unstemmed | Vasopressin Analog [V(4)Q(5)]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models |
title_short | Vasopressin Analog [V(4)Q(5)]dDAVP Exerts Cooperative Anticancer Effects in Combination With Low-Dose 5-Fluorouracil on Aggressive Colorectal Cancer Models |
title_sort | vasopressin analog [v(4)q(5)]ddavp exerts cooperative anticancer effects in combination with low-dose 5-fluorouracil on aggressive colorectal cancer models |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10681791/ https://www.ncbi.nlm.nih.gov/pubmed/38022396 http://dx.doi.org/10.14740/wjon1715 |
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