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344 The Potential Benefits of Using Senolytics in Colorectal Cancer Treatment

OBJECTIVES/GOALS: Anti-cancer therapies, such as chemotherapy, can induce senescence. Senescent cells may produce factors that can promote tumor progression. In this study, we will investigate the effect of senolytics and anti-cancer treatment on fibroblasts, which are a part of the tumor microenvir...

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Autores principales: Gallegos, Valerie, Rowdo, Florencia Madorsky, White, Jessica, Kuo, Hui-Hsuan, Podaza, Enrique, Martin, Laura, Elemento, Olivier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cambridge University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10129697/
http://dx.doi.org/10.1017/cts.2023.388
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author Gallegos, Valerie
Rowdo, Florencia Madorsky
White, Jessica
Kuo, Hui-Hsuan
Podaza, Enrique
Martin, Laura
Elemento, Olivier
author_facet Gallegos, Valerie
Rowdo, Florencia Madorsky
White, Jessica
Kuo, Hui-Hsuan
Podaza, Enrique
Martin, Laura
Elemento, Olivier
author_sort Gallegos, Valerie
collection PubMed
description OBJECTIVES/GOALS: Anti-cancer therapies, such as chemotherapy, can induce senescence. Senescent cells may produce factors that can promote tumor progression. In this study, we will investigate the effect of senolytics and anti-cancer treatment on fibroblasts, which are a part of the tumor microenvironment, and patient-derived colorectal cancer organoids. METHODS/STUDY POPULATION: We will induce senescence in fibroblast lines via irradation. Induction of senescence will be confirmed by monitoring SASP production, changes in morphology and proliferation rates, and senescence-associated b-galactosidase activity. To investigate the efficacy of senolytics on senescence-induced fibroblasts and CRC tumor organoids, we will creat a dose response curve and calculate IC50 values for proliferating fibroblast, senescent fibroblasts and CRC organoids. To identify the synergistic effects of anti-cancer and senolytic compounds, including Navitoclax and Dasatinib, on fibroblasts and CRC organoids, we will create dose matrixes using senolytics at concentrations that were shown to have senolytic activity and drugs from an anti-cancer library. RESULTS/ANTICIPATED RESULTS: If senescence is induced in the fibroblast lines, we expect to see no changes in confluency over 4 days, the morphology will change from a thin, spindly shape to a flattened shape, and senescence-associated b-galactosidase activity will be observed. After the fibroblast lines are treated with potential senolytic compounds, we would expect to see decreased viability in the senescence-induced fibroblast lines when compared to proliferating fibroblast lines. We predict that the viability of CRC organoid lines will slightly decrease at high concentrations of the senolytic due to overall toxicity. We expect that the senolytic and anti-cancer compounds will have a synergistic effect. Senolytic activity could reduce the senescent cell population that was developed in response to anti-cancer therapy. DISCUSSION/SIGNIFICANCE: There is an increased interest in identifying compounds that selectively promote apoptosis in senescent cells. This study uses a cell-based approach to validate senolytic activity of compounds with senolytic potential in senescence-induced fibroblast lines and investigates the synergistic effects of senolytics and anti-cancer compounds on CRC.
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spelling pubmed-101296972023-04-26 344 The Potential Benefits of Using Senolytics in Colorectal Cancer Treatment Gallegos, Valerie Rowdo, Florencia Madorsky White, Jessica Kuo, Hui-Hsuan Podaza, Enrique Martin, Laura Elemento, Olivier J Clin Transl Sci Precision Medicine/Health OBJECTIVES/GOALS: Anti-cancer therapies, such as chemotherapy, can induce senescence. Senescent cells may produce factors that can promote tumor progression. In this study, we will investigate the effect of senolytics and anti-cancer treatment on fibroblasts, which are a part of the tumor microenvironment, and patient-derived colorectal cancer organoids. METHODS/STUDY POPULATION: We will induce senescence in fibroblast lines via irradation. Induction of senescence will be confirmed by monitoring SASP production, changes in morphology and proliferation rates, and senescence-associated b-galactosidase activity. To investigate the efficacy of senolytics on senescence-induced fibroblasts and CRC tumor organoids, we will creat a dose response curve and calculate IC50 values for proliferating fibroblast, senescent fibroblasts and CRC organoids. To identify the synergistic effects of anti-cancer and senolytic compounds, including Navitoclax and Dasatinib, on fibroblasts and CRC organoids, we will create dose matrixes using senolytics at concentrations that were shown to have senolytic activity and drugs from an anti-cancer library. RESULTS/ANTICIPATED RESULTS: If senescence is induced in the fibroblast lines, we expect to see no changes in confluency over 4 days, the morphology will change from a thin, spindly shape to a flattened shape, and senescence-associated b-galactosidase activity will be observed. After the fibroblast lines are treated with potential senolytic compounds, we would expect to see decreased viability in the senescence-induced fibroblast lines when compared to proliferating fibroblast lines. We predict that the viability of CRC organoid lines will slightly decrease at high concentrations of the senolytic due to overall toxicity. We expect that the senolytic and anti-cancer compounds will have a synergistic effect. Senolytic activity could reduce the senescent cell population that was developed in response to anti-cancer therapy. DISCUSSION/SIGNIFICANCE: There is an increased interest in identifying compounds that selectively promote apoptosis in senescent cells. This study uses a cell-based approach to validate senolytic activity of compounds with senolytic potential in senescence-induced fibroblast lines and investigates the synergistic effects of senolytics and anti-cancer compounds on CRC. Cambridge University Press 2023-04-24 /pmc/articles/PMC10129697/ http://dx.doi.org/10.1017/cts.2023.388 Text en © The Association for Clinical and Translational Science 2023 https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
spellingShingle Precision Medicine/Health
Gallegos, Valerie
Rowdo, Florencia Madorsky
White, Jessica
Kuo, Hui-Hsuan
Podaza, Enrique
Martin, Laura
Elemento, Olivier
344 The Potential Benefits of Using Senolytics in Colorectal Cancer Treatment
title 344 The Potential Benefits of Using Senolytics in Colorectal Cancer Treatment
title_full 344 The Potential Benefits of Using Senolytics in Colorectal Cancer Treatment
title_fullStr 344 The Potential Benefits of Using Senolytics in Colorectal Cancer Treatment
title_full_unstemmed 344 The Potential Benefits of Using Senolytics in Colorectal Cancer Treatment
title_short 344 The Potential Benefits of Using Senolytics in Colorectal Cancer Treatment
title_sort 344 the potential benefits of using senolytics in colorectal cancer treatment
topic Precision Medicine/Health
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10129697/
http://dx.doi.org/10.1017/cts.2023.388
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