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Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)

SIMPLE SUMMARY: SBI-46, an antiandrogen-equipped histone deacetylase inhibitor, is the lead compound developed for targeting castration-resistant prostate cancer (CRPC). We determined the anticancer effect of SBI-46 on in vitro and in vivo models of CRPC. In our results, SBI-46 downregulates AR and...

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Autores principales: Chandrasekaran, Balaji, Tapadar, Subhasish, Wu, Bocheng, Saran, Uttara, Tyagi, Ashish, Johnston, Alexis, Gaul, David A., Oyelere, Adegboyega K., Damodaran, Chendil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10046692/
https://www.ncbi.nlm.nih.gov/pubmed/36980655
http://dx.doi.org/10.3390/cancers15061769
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author Chandrasekaran, Balaji
Tapadar, Subhasish
Wu, Bocheng
Saran, Uttara
Tyagi, Ashish
Johnston, Alexis
Gaul, David A.
Oyelere, Adegboyega K.
Damodaran, Chendil
author_facet Chandrasekaran, Balaji
Tapadar, Subhasish
Wu, Bocheng
Saran, Uttara
Tyagi, Ashish
Johnston, Alexis
Gaul, David A.
Oyelere, Adegboyega K.
Damodaran, Chendil
author_sort Chandrasekaran, Balaji
collection PubMed
description SIMPLE SUMMARY: SBI-46, an antiandrogen-equipped histone deacetylase inhibitor, is the lead compound developed for targeting castration-resistant prostate cancer (CRPC). We determined the anticancer effect of SBI-46 on in vitro and in vivo models of CRPC. In our results, SBI-46 downregulates AR and AR-splice variant (SV) expression and its downstream target genes in CRPC cells. Additionally, SBI-46 inhibits AR expression and nuclear localization in the presence of DHT. We further demonstrated that SBI-46 induces apoptosis by activating the pro-apoptotic genes Bax, cleaved PARP, and cleaved caspase-9, as well as downregulating the expression of the antiapoptotic genes Bcl2 and BCl-xL. Additionally, the oral administration of SBI-46 abrogates the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV. Finally, our results demonstrate that SBI-46 exerts an anticancer effect by inhibiting AR and AR-SV in preclinical models of CRPC. ABSTRACT: Background: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). Methods: Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. Results: While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR(+) CRPC cells but not AR(-) CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR(+) and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. Conclusion: These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC.
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spelling pubmed-100466922023-03-29 Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC) Chandrasekaran, Balaji Tapadar, Subhasish Wu, Bocheng Saran, Uttara Tyagi, Ashish Johnston, Alexis Gaul, David A. Oyelere, Adegboyega K. Damodaran, Chendil Cancers (Basel) Article SIMPLE SUMMARY: SBI-46, an antiandrogen-equipped histone deacetylase inhibitor, is the lead compound developed for targeting castration-resistant prostate cancer (CRPC). We determined the anticancer effect of SBI-46 on in vitro and in vivo models of CRPC. In our results, SBI-46 downregulates AR and AR-splice variant (SV) expression and its downstream target genes in CRPC cells. Additionally, SBI-46 inhibits AR expression and nuclear localization in the presence of DHT. We further demonstrated that SBI-46 induces apoptosis by activating the pro-apoptotic genes Bax, cleaved PARP, and cleaved caspase-9, as well as downregulating the expression of the antiapoptotic genes Bcl2 and BCl-xL. Additionally, the oral administration of SBI-46 abrogates the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV. Finally, our results demonstrate that SBI-46 exerts an anticancer effect by inhibiting AR and AR-SV in preclinical models of CRPC. ABSTRACT: Background: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). Methods: Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. Results: While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR(+) CRPC cells but not AR(-) CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR(+) and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. Conclusion: These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC. MDPI 2023-03-15 /pmc/articles/PMC10046692/ /pubmed/36980655 http://dx.doi.org/10.3390/cancers15061769 Text en © 2023 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
Chandrasekaran, Balaji
Tapadar, Subhasish
Wu, Bocheng
Saran, Uttara
Tyagi, Ashish
Johnston, Alexis
Gaul, David A.
Oyelere, Adegboyega K.
Damodaran, Chendil
Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)
title Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)
title_full Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)
title_fullStr Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)
title_full_unstemmed Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)
title_short Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)
title_sort antiandrogen-equipped histone deacetylase inhibitors selectively inhibit androgen receptor (ar) and ar-splice variant (ar-sv) in castration-resistant prostate cancer (crpc)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10046692/
https://www.ncbi.nlm.nih.gov/pubmed/36980655
http://dx.doi.org/10.3390/cancers15061769
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