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55484 Dual activation of CAR and Nrf2 improves the efficacy: toxicity ratio of cyclophosphamide and doxorubicin-based treatment of TNBC

ABSTRACT IMPACT: Triple negative breast cancer (TNBC) affects 10-20% of women with breast cancer and is biologically more aggressive than other subtypes. The novel compound we have developed, DL7076, would give clinicians a vital strategy to improve the commonly used cyclophosphamide (CPA) and doxor...

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Autores principales: Stern, Sydney, Liang, Dongdong, Li, Linhao, Kurian, Ritika, Lynch, Caitlin, Heyward, Scott, Kareem, Ajoke, Chun, Young, Hong, Charles, Xue, Fengtian, Wang, Hongbing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cambridge University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828015/
http://dx.doi.org/10.1017/cts.2021.653
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author Stern, Sydney
Liang, Dongdong
Li, Linhao
Kurian, Ritika
Lynch, Caitlin
Heyward, Scott
Kareem, Ajoke
Chun, Young
Hong, Charles
Xue, Fengtian
Wang, Hongbing
author_facet Stern, Sydney
Liang, Dongdong
Li, Linhao
Kurian, Ritika
Lynch, Caitlin
Heyward, Scott
Kareem, Ajoke
Chun, Young
Hong, Charles
Xue, Fengtian
Wang, Hongbing
author_sort Stern, Sydney
collection PubMed
description ABSTRACT IMPACT: Triple negative breast cancer (TNBC) affects 10-20% of women with breast cancer and is biologically more aggressive than other subtypes. The novel compound we have developed, DL7076, would give clinicians a vital strategy to improve the commonly used cyclophosphamide (CPA) and doxorubicin (DOX) regimen in the treatment of TNBC. OBJECTIVES/GOALS: The objective of this research project is to develop a novel compound which can activate both 1) the constitutive androstane receptor (CAR) and subsequently enhance the CYP2B6-mediated activation of CPA, and 2) the nuclear factor erythroid- related factor-2 (Nrf2) leading to the cardiomyocyte protection from DOX-associated cardiotoxicity. METHODS/STUDY POPULATION: Following the identification of the compound candidate, DL7076 was evaluated for tissue specific induction of CAR and Nrf2 using qPCR, western blot analysis, and luciferase reporter assays. Further, we have developed a multicellular coculture model incorporating human primary hepatocytes for metabolism, TNBC spheroids as the target, and cardiomyocytes as a side target of DOX. We have investigated the anticancer effects of CPA/DOX on TNBC cells and the toxic effects on cardiomyocytes with/without a CAR-Nrf2 activator, in a multicellular environment where hepatic metabolism is well-retained. RESULTS/ANTICIPATED RESULTS: We found that our dual activator of CAR and Nrf2, DL7076, exhibits tissue specific induction of CAR and Nrf2. Inclusion of DL7076 in combination with the CPA/DOX regimen improves anticancer efficacy, through the subsequent increase in the formation of the active CPA metabolite. With the addition of DL7076, DOX-mediated off-target cardiotoxicity was markedly reduced. Lastly, utilizing the novel coculture system with human primary hepatocytes, TNBC spheroids, and cardiomyocytes, the inclusion of DL7076 to the CPA/DOX regimen shows decreased spheroid viability and improved cardiomyocyte viability and function. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our findings suggest that DL7076 can facilitate DOX/CPA containing regimens by increasing CAR-mediated metabolism and subsequent CPA bioactivation while selectively protecting cardiomyocytes from DOX-induced toxicity. This research is expected to translate our basic scientific findings into therapeutic interventions for women with TNBC.
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spelling pubmed-88280152022-02-28 55484 Dual activation of CAR and Nrf2 improves the efficacy: toxicity ratio of cyclophosphamide and doxorubicin-based treatment of TNBC Stern, Sydney Liang, Dongdong Li, Linhao Kurian, Ritika Lynch, Caitlin Heyward, Scott Kareem, Ajoke Chun, Young Hong, Charles Xue, Fengtian Wang, Hongbing J Clin Transl Sci Mechanistic Basic to Clinical ABSTRACT IMPACT: Triple negative breast cancer (TNBC) affects 10-20% of women with breast cancer and is biologically more aggressive than other subtypes. The novel compound we have developed, DL7076, would give clinicians a vital strategy to improve the commonly used cyclophosphamide (CPA) and doxorubicin (DOX) regimen in the treatment of TNBC. OBJECTIVES/GOALS: The objective of this research project is to develop a novel compound which can activate both 1) the constitutive androstane receptor (CAR) and subsequently enhance the CYP2B6-mediated activation of CPA, and 2) the nuclear factor erythroid- related factor-2 (Nrf2) leading to the cardiomyocyte protection from DOX-associated cardiotoxicity. METHODS/STUDY POPULATION: Following the identification of the compound candidate, DL7076 was evaluated for tissue specific induction of CAR and Nrf2 using qPCR, western blot analysis, and luciferase reporter assays. Further, we have developed a multicellular coculture model incorporating human primary hepatocytes for metabolism, TNBC spheroids as the target, and cardiomyocytes as a side target of DOX. We have investigated the anticancer effects of CPA/DOX on TNBC cells and the toxic effects on cardiomyocytes with/without a CAR-Nrf2 activator, in a multicellular environment where hepatic metabolism is well-retained. RESULTS/ANTICIPATED RESULTS: We found that our dual activator of CAR and Nrf2, DL7076, exhibits tissue specific induction of CAR and Nrf2. Inclusion of DL7076 in combination with the CPA/DOX regimen improves anticancer efficacy, through the subsequent increase in the formation of the active CPA metabolite. With the addition of DL7076, DOX-mediated off-target cardiotoxicity was markedly reduced. Lastly, utilizing the novel coculture system with human primary hepatocytes, TNBC spheroids, and cardiomyocytes, the inclusion of DL7076 to the CPA/DOX regimen shows decreased spheroid viability and improved cardiomyocyte viability and function. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our findings suggest that DL7076 can facilitate DOX/CPA containing regimens by increasing CAR-mediated metabolism and subsequent CPA bioactivation while selectively protecting cardiomyocytes from DOX-induced toxicity. This research is expected to translate our basic scientific findings into therapeutic interventions for women with TNBC. Cambridge University Press 2021-03-30 /pmc/articles/PMC8828015/ http://dx.doi.org/10.1017/cts.2021.653 Text en © The Association for Clinical and Translational Science 2021 https://creativecommons.org/licenses/by/4.0/This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Mechanistic Basic to Clinical
Stern, Sydney
Liang, Dongdong
Li, Linhao
Kurian, Ritika
Lynch, Caitlin
Heyward, Scott
Kareem, Ajoke
Chun, Young
Hong, Charles
Xue, Fengtian
Wang, Hongbing
55484 Dual activation of CAR and Nrf2 improves the efficacy: toxicity ratio of cyclophosphamide and doxorubicin-based treatment of TNBC
title 55484 Dual activation of CAR and Nrf2 improves the efficacy: toxicity ratio of cyclophosphamide and doxorubicin-based treatment of TNBC
title_full 55484 Dual activation of CAR and Nrf2 improves the efficacy: toxicity ratio of cyclophosphamide and doxorubicin-based treatment of TNBC
title_fullStr 55484 Dual activation of CAR and Nrf2 improves the efficacy: toxicity ratio of cyclophosphamide and doxorubicin-based treatment of TNBC
title_full_unstemmed 55484 Dual activation of CAR and Nrf2 improves the efficacy: toxicity ratio of cyclophosphamide and doxorubicin-based treatment of TNBC
title_short 55484 Dual activation of CAR and Nrf2 improves the efficacy: toxicity ratio of cyclophosphamide and doxorubicin-based treatment of TNBC
title_sort 55484 dual activation of car and nrf2 improves the efficacy: toxicity ratio of cyclophosphamide and doxorubicin-based treatment of tnbc
topic Mechanistic Basic to Clinical
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828015/
http://dx.doi.org/10.1017/cts.2021.653
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