The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth
Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis (c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein stru...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/15/3851 |
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| author | Sanjeev Shukla Carlos Riveros Mohammed Al-Toubat Jonathan Chardon-Robles Teruko Osumi Samuel Serrano Adam M. Kase Joachim L. Petit Nathalie Meurice Justyna Gleba John A. Copland Jay Chauhan Steven Fletcher K. C. Balaji |
| author_facet | Sanjeev Shukla Carlos Riveros Mohammed Al-Toubat Jonathan Chardon-Robles Teruko Osumi Samuel Serrano Adam M. Kase Joachim L. Petit Nathalie Meurice Justyna Gleba John A. Copland Jay Chauhan Steven Fletcher K. C. Balaji |
| author_sort | Sanjeev Shukla |
| collection | DOAJ |
| description | Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis (c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein structure and predominant nuclear localization. The epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1. MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration-sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by the de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11, and serine 216 amino acid residues in β-Catenin, snail, and cell division cycle 25c (CDC25c) proteins, respectively. The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC<sub>50</sub> in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation. |
| first_indexed | 2024-03-11T00:30:07Z |
| format | Article |
| id | doaj.art-2c8a4af7601241e7a5634c99438f6fad |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T00:30:07Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2c8a4af7601241e7a5634c99438f6fad2023-11-18T22:42:16ZengMDPI AGCancers2072-66942023-07-011515385110.3390/cancers15153851The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer GrowthSanjeev Shukla0Carlos Riveros1Mohammed Al-Toubat2Jonathan Chardon-Robles3Teruko Osumi4Samuel Serrano5Adam M. Kase6Joachim L. Petit7Nathalie Meurice8Justyna Gleba9John A. Copland10Jay Chauhan11Steven Fletcher12K. C. Balaji13Department of Urology, University of Florida Health, Jacksonville, FL 32209, USADepartment of Urology, University of Florida Health, Jacksonville, FL 32209, USADepartment of Urology, University of Florida Health, Jacksonville, FL 32209, USADepartment of Urology, University of Florida Health, Jacksonville, FL 32209, USADepartment of Urology, University of Florida Health, Jacksonville, FL 32209, USADepartment of Urology, University of Florida Health, Jacksonville, FL 32209, USADepartment of Hematology Oncology, Mayo Clinic, Jacksonville, FL 32224, USADepartment of Hematology Oncology, Mayo Clinic, Jacksonville, FL 32224, USADepartment of Hematology Oncology, Mayo Clinic, Jacksonville, FL 32224, USACancer Biology Department, Mayo Clinic, Jacksonville, FL 32224, USACancer Biology Department, Mayo Clinic, Jacksonville, FL 32224, USADepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USADepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USADepartment of Urology, University of Florida Health, Jacksonville, FL 32209, USABromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis (c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein structure and predominant nuclear localization. The epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1. MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration-sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by the de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11, and serine 216 amino acid residues in β-Catenin, snail, and cell division cycle 25c (CDC25c) proteins, respectively. The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC<sub>50</sub> in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation.https://www.mdpi.com/2072-6694/15/15/3851bromodomain inhibitorsMT-1prostate cancerpatient-derived xenograftsc-Myc |
| spellingShingle | Sanjeev Shukla Carlos Riveros Mohammed Al-Toubat Jonathan Chardon-Robles Teruko Osumi Samuel Serrano Adam M. Kase Joachim L. Petit Nathalie Meurice Justyna Gleba John A. Copland Jay Chauhan Steven Fletcher K. C. Balaji The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth Cancers bromodomain inhibitors MT-1 prostate cancer patient-derived xenografts c-Myc |
| title | The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth |
| title_full | The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth |
| title_fullStr | The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth |
| title_full_unstemmed | The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth |
| title_short | The Bivalent Bromodomain Inhibitor MT-1 Inhibits Prostate Cancer Growth |
| title_sort | bivalent bromodomain inhibitor mt 1 inhibits prostate cancer growth |
| topic | bromodomain inhibitors MT-1 prostate cancer patient-derived xenografts c-Myc |
| url | https://www.mdpi.com/2072-6694/15/15/3851 |
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