Cargando…

AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model

Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) from ATP and GTP. 2′3′-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory c...

Descripción completa

Detalles Bibliográficos
Autores principales: Goswami, Avijit, Deb, Barnali, Goyal, Sandeep, Gosavi, Abhishek, Mali, Mukund, Martis, Ashwita M., Khurana, Princy, Gangar, Mukesh, Raykar, Digambar, Mohanty, Ankita, Kulkarni, Aditya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9573294/
https://www.ncbi.nlm.nih.gov/pubmed/36235254
http://dx.doi.org/10.3390/molecules27196721
_version_ 1784810833386143744
author Goswami, Avijit
Deb, Barnali
Goyal, Sandeep
Gosavi, Abhishek
Mali, Mukund
Martis, Ashwita M.
Khurana, Princy
Gangar, Mukesh
Raykar, Digambar
Mohanty, Ankita
Kulkarni, Aditya
author_facet Goswami, Avijit
Deb, Barnali
Goyal, Sandeep
Gosavi, Abhishek
Mali, Mukund
Martis, Ashwita M.
Khurana, Princy
Gangar, Mukesh
Raykar, Digambar
Mohanty, Ankita
Kulkarni, Aditya
author_sort Goswami, Avijit
collection PubMed
description Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) from ATP and GTP. 2′3′-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates the STING pathway by hydrolyzing 2′3′-cGAMP. It has been established that the cGAS–STING pathway plays a major role in inhibiting tumor growth by upregulating T cell response. Herein, we demonstrate that AVA-NP-695, a selective and highly potent ENPP1 inhibitor, apart from the immunomodulatory effect also modulates cancer metastasis by negatively regulating epithelial–mesenchymal transition (EMT). We established that the combined addition of 2′3′-cGAMP and AVA-NP-695 significantly abrogated the transforming growth factor beta (TGF-ꞵ)-induced EMT in MDA-MB-231 cells. Finally, results from the in vivo study showed superior tumor growth inhibition and impact on tumor metastasis of AVA-NP-695 compared to Olaparib and PD-1 in a syngeneic 4T1 breast cancer mouse model. The translation of efficacy from in vitro to in vivo 4T1 tumor model provides a strong rationale for the therapeutic potential of AVA-NP-695 against triple-negative breast cancer (TNBC) as an immunomodulatory and anti-metastatic agent.
format Online
Article
Text
id pubmed-9573294
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-95732942022-10-17 AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model Goswami, Avijit Deb, Barnali Goyal, Sandeep Gosavi, Abhishek Mali, Mukund Martis, Ashwita M. Khurana, Princy Gangar, Mukesh Raykar, Digambar Mohanty, Ankita Kulkarni, Aditya Molecules Article Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) from ATP and GTP. 2′3′-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates the STING pathway by hydrolyzing 2′3′-cGAMP. It has been established that the cGAS–STING pathway plays a major role in inhibiting tumor growth by upregulating T cell response. Herein, we demonstrate that AVA-NP-695, a selective and highly potent ENPP1 inhibitor, apart from the immunomodulatory effect also modulates cancer metastasis by negatively regulating epithelial–mesenchymal transition (EMT). We established that the combined addition of 2′3′-cGAMP and AVA-NP-695 significantly abrogated the transforming growth factor beta (TGF-ꞵ)-induced EMT in MDA-MB-231 cells. Finally, results from the in vivo study showed superior tumor growth inhibition and impact on tumor metastasis of AVA-NP-695 compared to Olaparib and PD-1 in a syngeneic 4T1 breast cancer mouse model. The translation of efficacy from in vitro to in vivo 4T1 tumor model provides a strong rationale for the therapeutic potential of AVA-NP-695 against triple-negative breast cancer (TNBC) as an immunomodulatory and anti-metastatic agent. MDPI 2022-10-09 /pmc/articles/PMC9573294/ /pubmed/36235254 http://dx.doi.org/10.3390/molecules27196721 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
Goswami, Avijit
Deb, Barnali
Goyal, Sandeep
Gosavi, Abhishek
Mali, Mukund
Martis, Ashwita M.
Khurana, Princy
Gangar, Mukesh
Raykar, Digambar
Mohanty, Ankita
Kulkarni, Aditya
AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model
title AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model
title_full AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model
title_fullStr AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model
title_full_unstemmed AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model
title_short AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model
title_sort ava-np-695 selectively inhibits enpp1 to activate sting pathway and abrogate tumor metastasis in 4t1 breast cancer syngeneic mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9573294/
https://www.ncbi.nlm.nih.gov/pubmed/36235254
http://dx.doi.org/10.3390/molecules27196721
work_keys_str_mv AT goswamiavijit avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT debbarnali avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT goyalsandeep avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT gosaviabhishek avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT malimukund avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT martisashwitam avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT khuranaprincy avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT gangarmukesh avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT raykardigambar avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT mohantyankita avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel
AT kulkarniaditya avanp695selectivelyinhibitsenpp1toactivatestingpathwayandabrogatetumormetastasisin4t1breastcancersyngeneicmousemodel