YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacy
Introduction: Prostate cancer is the second leading cause of cancer death among men in the United States. Castration-Resistant Prostate Cancer (CRPC) often develops resistance to androgen deprivation therapy. Resistance in CRPC is often driven by AR variants and glucocorticoid receptor (GR). Thus, d...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-10-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1244655/full |
| _version_ | 1797666498474409984 |
|---|---|
| author | Wing Lam Mohammad Arammash Wei Cai Wei Cai Fulan Guan Zaoli Jiang Shwu-Huey Liu Peikwen Cheng Yung-Chi Cheng |
| author_facet | Wing Lam Mohammad Arammash Wei Cai Wei Cai Fulan Guan Zaoli Jiang Shwu-Huey Liu Peikwen Cheng Yung-Chi Cheng |
| author_sort | Wing Lam |
| collection | DOAJ |
| description | Introduction: Prostate cancer is the second leading cause of cancer death among men in the United States. Castration-Resistant Prostate Cancer (CRPC) often develops resistance to androgen deprivation therapy. Resistance in CRPC is often driven by AR variants and glucocorticoid receptor (GR). Thus, drugs that target both could be vital in overcoming resistance.Methods: Utilizing the STAR Drug Discovery Platform, three hundred medicinal plant extracts were examined across 25 signaling pathways to identify potential drug candidates. Effects of the botanical drug YIV-818-A, derived from optimized water extracts of Rubia cordifolia (R.C.), on Dihydrotestosterone (DHT) or Dexamethasone (DEX) induced luciferase activity were assessed in 22RV1 cells harboring the ARE luciferase reporter. Furthermore, the key active compounds in YIV-818-A were identified through activity guided purification. The inhibitory effects of YIV-818-A, RA-V, and RA-VII on AR and GR activities, their impact on AR target genes, and their roles in modifying epigenetic status were investigated. Finally, the synergistic effects of these compounds with established CRPC drugs were evaluated both in vitro and in vivo.Results: YIV-818-A was found to effectively inhibit DHT or DEX induced luciferase activity in 22RV1 cells. Deoxybouvardin (RA-V) was identified as the key active compound responsible for inhibiting AR and GR activities. Both YIV-818-A and RA-V, along with RA-VII, effectively downregulated AR and AR-V proteins through inhibiting protein synthesis, impacted the expression of AR target genes, and modified the epigenetic status by reducing levels of Bromodomain and Extra-Terminal proteins (Brd2/Brd4) and H3K27Ac. Furthermore, these compounds exhibited synergistic effects with apalutamide, darolutamide, or enzalutamide, and suppressed AR mediated luciferase activity of 22RV1 cells. Co-administration of YIV-818-A and enzalutamide led to a significant reduction of 22RV1 tumor growth in vivo. Different sources of R.C. had variable levels of RA-V, correlating with their potency in AR inhibition.Discussion: YIV-818-A, RA-V, and RA-VII show considerable promise in addressing drug resistance in CRPC by targeting both AR protein and GR function, along with modulation of vital epigenetic markers. Given the established safety profile of YIV-818-A, these findings suggest its potential as a chemopreventive agent and a robust anti-prostate cancer drug. |
| first_indexed | 2024-03-11T20:00:13Z |
| format | Article |
| id | doaj.art-346c166ea134490baec8ca16f0874b74 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-11T20:00:13Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-346c166ea134490baec8ca16f0874b742023-10-04T08:35:21ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-10-011410.3389/fphar.2023.12446551244655YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacyWing Lam0Mohammad Arammash1Wei Cai2Wei Cai3Fulan Guan4Zaoli Jiang5Shwu-Huey Liu6Peikwen Cheng7Yung-Chi Cheng8Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT, United StatesSchool of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua, ChinaDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT, United StatesYiviva, Inc, New York, NY, United StatesYiviva, Inc, New York, NY, United StatesDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT, United StatesIntroduction: Prostate cancer is the second leading cause of cancer death among men in the United States. Castration-Resistant Prostate Cancer (CRPC) often develops resistance to androgen deprivation therapy. Resistance in CRPC is often driven by AR variants and glucocorticoid receptor (GR). Thus, drugs that target both could be vital in overcoming resistance.Methods: Utilizing the STAR Drug Discovery Platform, three hundred medicinal plant extracts were examined across 25 signaling pathways to identify potential drug candidates. Effects of the botanical drug YIV-818-A, derived from optimized water extracts of Rubia cordifolia (R.C.), on Dihydrotestosterone (DHT) or Dexamethasone (DEX) induced luciferase activity were assessed in 22RV1 cells harboring the ARE luciferase reporter. Furthermore, the key active compounds in YIV-818-A were identified through activity guided purification. The inhibitory effects of YIV-818-A, RA-V, and RA-VII on AR and GR activities, their impact on AR target genes, and their roles in modifying epigenetic status were investigated. Finally, the synergistic effects of these compounds with established CRPC drugs were evaluated both in vitro and in vivo.Results: YIV-818-A was found to effectively inhibit DHT or DEX induced luciferase activity in 22RV1 cells. Deoxybouvardin (RA-V) was identified as the key active compound responsible for inhibiting AR and GR activities. Both YIV-818-A and RA-V, along with RA-VII, effectively downregulated AR and AR-V proteins through inhibiting protein synthesis, impacted the expression of AR target genes, and modified the epigenetic status by reducing levels of Bromodomain and Extra-Terminal proteins (Brd2/Brd4) and H3K27Ac. Furthermore, these compounds exhibited synergistic effects with apalutamide, darolutamide, or enzalutamide, and suppressed AR mediated luciferase activity of 22RV1 cells. Co-administration of YIV-818-A and enzalutamide led to a significant reduction of 22RV1 tumor growth in vivo. Different sources of R.C. had variable levels of RA-V, correlating with their potency in AR inhibition.Discussion: YIV-818-A, RA-V, and RA-VII show considerable promise in addressing drug resistance in CRPC by targeting both AR protein and GR function, along with modulation of vital epigenetic markers. Given the established safety profile of YIV-818-A, these findings suggest its potential as a chemopreventive agent and a robust anti-prostate cancer drug.https://www.frontiersin.org/articles/10.3389/fphar.2023.1244655/fullYIV-818-AARGRprostate cancerapalutamidedarolutamide |
| spellingShingle | Wing Lam Mohammad Arammash Wei Cai Wei Cai Fulan Guan Zaoli Jiang Shwu-Huey Liu Peikwen Cheng Yung-Chi Cheng YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacy Frontiers in Pharmacology YIV-818-A AR GR prostate cancer apalutamide darolutamide |
| title | YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacy |
| title_full | YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacy |
| title_fullStr | YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacy |
| title_full_unstemmed | YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacy |
| title_short | YIV-818-A: a novel therapeutic agent in prostate cancer management through androgen receptor downregulation, glucocorticoid receptor inhibition, epigenetic regulation, and enhancement of apalutamide, darolutamide, and enzalutamide efficacy |
| title_sort | yiv 818 a a novel therapeutic agent in prostate cancer management through androgen receptor downregulation glucocorticoid receptor inhibition epigenetic regulation and enhancement of apalutamide darolutamide and enzalutamide efficacy |
| topic | YIV-818-A AR GR prostate cancer apalutamide darolutamide |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1244655/full |
| work_keys_str_mv | AT winglam yiv818aanoveltherapeuticagentinprostatecancermanagementthroughandrogenreceptordownregulationglucocorticoidreceptorinhibitionepigeneticregulationandenhancementofapalutamidedarolutamideandenzalutamideefficacy AT mohammadarammash yiv818aanoveltherapeuticagentinprostatecancermanagementthroughandrogenreceptordownregulationglucocorticoidreceptorinhibitionepigeneticregulationandenhancementofapalutamidedarolutamideandenzalutamideefficacy AT weicai yiv818aanoveltherapeuticagentinprostatecancermanagementthroughandrogenreceptordownregulationglucocorticoidreceptorinhibitionepigeneticregulationandenhancementofapalutamidedarolutamideandenzalutamideefficacy AT weicai yiv818aanoveltherapeuticagentinprostatecancermanagementthroughandrogenreceptordownregulationglucocorticoidreceptorinhibitionepigeneticregulationandenhancementofapalutamidedarolutamideandenzalutamideefficacy AT fulanguan yiv818aanoveltherapeuticagentinprostatecancermanagementthroughandrogenreceptordownregulationglucocorticoidreceptorinhibitionepigeneticregulationandenhancementofapalutamidedarolutamideandenzalutamideefficacy AT zaolijiang yiv818aanoveltherapeuticagentinprostatecancermanagementthroughandrogenreceptordownregulationglucocorticoidreceptorinhibitionepigeneticregulationandenhancementofapalutamidedarolutamideandenzalutamideefficacy AT shwuhueyliu yiv818aanoveltherapeuticagentinprostatecancermanagementthroughandrogenreceptordownregulationglucocorticoidreceptorinhibitionepigeneticregulationandenhancementofapalutamidedarolutamideandenzalutamideefficacy AT peikwencheng yiv818aanoveltherapeuticagentinprostatecancermanagementthroughandrogenreceptordownregulationglucocorticoidreceptorinhibitionepigeneticregulationandenhancementofapalutamidedarolutamideandenzalutamideefficacy AT yungchicheng yiv818aanoveltherapeuticagentinprostatecancermanagementthroughandrogenreceptordownregulationglucocorticoidreceptorinhibitionepigeneticregulationandenhancementofapalutamidedarolutamideandenzalutamideefficacy |