A pyridinium-type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β-catenin

Primary effusion lymphoma (PEL) is defined as a rare subtype of non-Hodgkin's B cell lymphoma, which is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. PEL is an aggressive type of lymphoma and is frequently resistant to conventional chemotherapeutics...

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Autores principales: Kadota, Ayano, Moriguchi, Misato, Watanabe, Tadashi, Sekine, Yuichi, Nakamura, Shigeo, Yasuno, Takumi, Ohe, Tomoyuki, Mashino, Tadahiko, Fujimuro, Masahiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8771160/
https://www.ncbi.nlm.nih.gov/pubmed/35014678
http://dx.doi.org/10.3892/or.2022.8257
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author Kadota, Ayano
Moriguchi, Misato
Watanabe, Tadashi
Sekine, Yuichi
Nakamura, Shigeo
Yasuno, Takumi
Ohe, Tomoyuki
Mashino, Tadahiko
Fujimuro, Masahiro
author_facet Kadota, Ayano
Moriguchi, Misato
Watanabe, Tadashi
Sekine, Yuichi
Nakamura, Shigeo
Yasuno, Takumi
Ohe, Tomoyuki
Mashino, Tadahiko
Fujimuro, Masahiro
author_sort Kadota, Ayano
collection PubMed
description Primary effusion lymphoma (PEL) is defined as a rare subtype of non-Hodgkin's B cell lymphoma, which is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. PEL is an aggressive type of lymphoma and is frequently resistant to conventional chemotherapeutics. Therefore, the discovery of novel drug candidates for the treatment of PEL is of utmost importance. In order to discover potential novel anti-tumor compounds against PEL, the authors previously developed a pyrrolidinium-type fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide (derivative #1), which induced the apoptosis of PEL cells via caspase-9 activation. In the present study, the growth inhibitory effects of pyrrolidinium-type (derivatives #1 and #2), pyridinium-type (derivatives #3 and #5 to #9) and anilinium-type fullerene derivatives (derivative #4) against PEL cells were evaluated. This analysis revealed a pyridinium-type derivative (derivative #5; 3- 5′-(etho-xycarbonyl)-1′,5′-dihydro-2′H-[5,6]fullereno-C(60)-I(h)-[1,9-c]pyrrol-2′-yl]-1-methylpyridinium iodide), which exhibited antitumor activity against PEL cells via the downregulation of Wnt/β-catenin signaling. Derivative #5 suppressed the viability of KSHV-infected PEL cells compared with KSHV-uninfected B-lymphoma cells. Furthermore, derivative #5 induced the destabilization of β-catenin and suppressed β-catenin-TCF4 transcriptional activity in PEL cells. It is known that the constitutive activation of Wnt/β-catenin signaling is essential for the growth of KSHV-infected cells. The Wnt/β-catenin activation in KSHV-infected cells is mediated by KSHV latency-associated nuclear antigen (LANA). The data demonstrated that derivative #5 increased β-catenin phosphorylation, which resulted in β-catenin polyubiquitination and subsequent degradation. Thus, derivative #5 overcame LANA-mediated β-catenin stabilization. Furthermore, the administration of derivative #5 suppressed the development of PEL cells in the ascites of SCID mice with tumor xenografts derived from PEL cells. On the whole, these findings provide evidence that the pyridinium-type fullerene derivative #5 exhibits antitumor activity against PEL cells in vitro and in vivo. Thus, derivative #5 may be utilized as a novel therapeutic agent for the treatment of PEL.
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spelling pubmed-87711602022-02-03 A pyridinium-type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β-catenin Kadota, Ayano Moriguchi, Misato Watanabe, Tadashi Sekine, Yuichi Nakamura, Shigeo Yasuno, Takumi Ohe, Tomoyuki Mashino, Tadahiko Fujimuro, Masahiro Oncol Rep Articles Primary effusion lymphoma (PEL) is defined as a rare subtype of non-Hodgkin's B cell lymphoma, which is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. PEL is an aggressive type of lymphoma and is frequently resistant to conventional chemotherapeutics. Therefore, the discovery of novel drug candidates for the treatment of PEL is of utmost importance. In order to discover potential novel anti-tumor compounds against PEL, the authors previously developed a pyrrolidinium-type fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide (derivative #1), which induced the apoptosis of PEL cells via caspase-9 activation. In the present study, the growth inhibitory effects of pyrrolidinium-type (derivatives #1 and #2), pyridinium-type (derivatives #3 and #5 to #9) and anilinium-type fullerene derivatives (derivative #4) against PEL cells were evaluated. This analysis revealed a pyridinium-type derivative (derivative #5; 3- 5′-(etho-xycarbonyl)-1′,5′-dihydro-2′H-[5,6]fullereno-C(60)-I(h)-[1,9-c]pyrrol-2′-yl]-1-methylpyridinium iodide), which exhibited antitumor activity against PEL cells via the downregulation of Wnt/β-catenin signaling. Derivative #5 suppressed the viability of KSHV-infected PEL cells compared with KSHV-uninfected B-lymphoma cells. Furthermore, derivative #5 induced the destabilization of β-catenin and suppressed β-catenin-TCF4 transcriptional activity in PEL cells. It is known that the constitutive activation of Wnt/β-catenin signaling is essential for the growth of KSHV-infected cells. The Wnt/β-catenin activation in KSHV-infected cells is mediated by KSHV latency-associated nuclear antigen (LANA). The data demonstrated that derivative #5 increased β-catenin phosphorylation, which resulted in β-catenin polyubiquitination and subsequent degradation. Thus, derivative #5 overcame LANA-mediated β-catenin stabilization. Furthermore, the administration of derivative #5 suppressed the development of PEL cells in the ascites of SCID mice with tumor xenografts derived from PEL cells. On the whole, these findings provide evidence that the pyridinium-type fullerene derivative #5 exhibits antitumor activity against PEL cells in vitro and in vivo. Thus, derivative #5 may be utilized as a novel therapeutic agent for the treatment of PEL. D.A. Spandidos 2022-03 2022-01-05 /pmc/articles/PMC8771160/ /pubmed/35014678 http://dx.doi.org/10.3892/or.2022.8257 Text en Copyright: © Kadota et al. 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-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Kadota, Ayano
Moriguchi, Misato
Watanabe, Tadashi
Sekine, Yuichi
Nakamura, Shigeo
Yasuno, Takumi
Ohe, Tomoyuki
Mashino, Tadahiko
Fujimuro, Masahiro
A pyridinium-type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β-catenin
title A pyridinium-type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β-catenin
title_full A pyridinium-type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β-catenin
title_fullStr A pyridinium-type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β-catenin
title_full_unstemmed A pyridinium-type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β-catenin
title_short A pyridinium-type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the Wnt signaling pathway through the destabilization of β-catenin
title_sort pyridinium-type fullerene derivative suppresses primary effusion lymphoma cell viability via the downregulation of the wnt signaling pathway through the destabilization of β-catenin
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8771160/
https://www.ncbi.nlm.nih.gov/pubmed/35014678
http://dx.doi.org/10.3892/or.2022.8257
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