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Poojary KK, Kunhiraman JP, Madhvacharya VV, Kumari S, Krishna N, S SP, K RG, Mutalik S, Ghani NK, Kabekkodu SP, Prasad TSK, Adiga SK, Kalthur G. Bromodomain and extraterminal protein inhibitor JQ1 induces maturation arrest and disrupts the cytoplasmic organization in mouse oocytes under in vitro conditions. Sci Rep 2025; 15:13448. [PMID: 40251236 PMCID: PMC12008386 DOI: 10.1038/s41598-025-96687-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 03/31/2025] [Indexed: 04/20/2025] Open
Abstract
JQ1, a small cell-permeable molecule is known for its potent inhibitory action on bromodomain and extraterminal (BET) proteins. Although earlier studies have shown its inhibitory effect on male gametogenesis, limited information is available about its influence on oocyte development. Since BET genes are known to exhibit regulatory functions on oocyte development and maturation, the present study aimed to investigate the effect of JQ1 on oocyte developmental competence under in vitro conditions. Germinal vesicle (GV) stage oocytes were collected from adult Swiss albino mice and subjected to in vitro maturation (IVM) in the presence of various concentrations of JQ1 (25, 50, and 100 μM). The metaphase II (MII) stage oocytes were assessed for cytoplasmic organization and functional competence at 24 h after IVM. A significant decrease in nuclear maturation (at 50 and 100 μM), symmetric cytokinesis, altered distribution of mitochondria and cortical granules, poorly organized actin and meiotic spindle, misaligned chromosomes, and elevated endoplasmic reticulum (ER) stress and oxidative stress was observed in JQ1-exposed oocytes. Presence of N-acetyl cysteine (NAC), in IVM medium resulted in significant reduction in JQ1-induced oxidative stress and symmetric cytokinesis. Administration of JQ1 (50 mg/kg, intra peritoneal) to adult Swiss albino mice primed with pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) did not affect the ovulation. However, a high degree of oocyte degeneration, elevated intracellular reactive oxygen species (ROS), and GRP78 expression was observed in JQ1-administered mice. In conclusion, our study reveals that BET inhibitor JQ1 has detrimental effects on oocyte function and development.
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Affiliation(s)
- Keerthana Karunakar Poojary
- Centre of Excellence in Clinical Embryology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Jyolsna Ponnaratta Kunhiraman
- Division of Reproductive Biology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Vanishree Vasave Madhvacharya
- Division of Reproductive Biology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Sandhya Kumari
- Division of Reproductive Biology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Navami Krishna
- Department of Bioscience and Engineering, National Institute of Technology, Calicut, 673601, Kerala, India
| | - Suresh P S
- Department of Bioscience and Engineering, National Institute of Technology, Calicut, 673601, Kerala, India
| | - Rajanikant G K
- Department of Bioscience and Engineering, National Institute of Technology, Calicut, 673601, Kerala, India
| | - Srinivas Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Nadeem Khan Ghani
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Shama Prasada Kabekkodu
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Thottethodi Subrahmanya Keshava Prasad
- Center for Systems Biology and Molecular Medicine [An ICMR-Collaborating Centre of Excellence (ICMR-CCoE 2024)], Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Satish Kumar Adiga
- Centre of Excellence in Clinical Embryology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Guruprasad Kalthur
- Division of Reproductive Biology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India.
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2
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Dutta R, Devarajan A, Talluri A, Das R, Thayumanavan S. Dual-Action-Only PROTACs. J Am Chem Soc 2025; 147:9074-9078. [PMID: 40063962 DOI: 10.1021/jacs.5c00131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Proteolysis targeting chimera (PROTAC)-based degraders are highly potent pseudocatalytic drugs, but on-target off-site homing could yield undesirable consequences. We report here a generalizable AND-logic gated PROTAC, where the concurrent presence of two different disease-relevant endogenous stimuli liberates an active protein degrader. We design Dual-Action-Only PROTAC (DAO-PROTAC) molecules that are dormant and can only be activated in the presence of both hypoxia and cathepsin-L to degrade the protein of interest (POI). We also show that the dormancy of DAO-PROTACs translates to considerable mitigation of cytotoxicity, demonstrating the potential advantages over the corresponding free PROTAC and single-stimulus triggerable pro-PROTACs.
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Affiliation(s)
- Ranit Dutta
- Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
- Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
| | - Anirudh Devarajan
- Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
- Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
| | - Amelia Talluri
- Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
| | - Ritam Das
- Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
- Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
| | - S Thayumanavan
- Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
- Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States
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3
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Beter M, Pulkkinen HH, Örd T, Sormunen A, Kilpeläinen L, Dunford JE, Kaikkonen MU, Aavik E, Laham-Karam N, Oppermann U, Laakkonen JP, Ylä-Herttuala S. Epigenetic drug screening identifies enzyme inhibitors A-196 and TMP-269 as novel regulators of sprouting angiogenesis. Sci Rep 2025; 15:1628. [PMID: 39794417 PMCID: PMC11724134 DOI: 10.1038/s41598-024-84603-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Epigenetic therapy has gained interest in treating cardiovascular diseases, but preclinical studies often encounter challenges with cell-type-specific effects or batch-to-batch variation, which have limited identification of novel drug candidates targeting angiogenesis. To address these limitations and improve the reproducibility of epigenetic drug screening, we redesigned a 3D in vitro fibrin bead assay to utilize immortalized human aortic endothelial cells (TeloHAECs) and screened a focused compound library with 105 agents. Compared to the established model using primary human umbilical vein endothelial cells, TeloHAECs needed a higher-density fibrin gel for optimal sprouting, successfully forming sprouts under both normoxic and hypoxic cell culture conditions. We identified two epigenetic enzyme inhibitors as novel regulators of sprouting angiogenesis: A196, a selective SUV4-20H1/H2 inhibitor, demonstrated pro-angiogenic effects through increased H4K20me1 levels and upregulation of cell cycle associated genes, including MCM2 and CDK4. In contrast TMP-269, a selective class IIa HDAC inhibitor, exhibited anti-angiogenic effects by downregulating angiogenesis-related proteins and upregulating pro-inflammatory signaling. These findings highlight the suitability of the modified TeloHAEC fibrin bead assay for drug screening purposes and reveal both pro-angiogenic and anti-angiogenic drug candidates with therapeutic potential.
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Affiliation(s)
- M Beter
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - H H Pulkkinen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - T Örd
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - A Sormunen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - L Kilpeläinen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - J E Dunford
- Botnar Research Centre, Oxford NIHR BRU, University of Oxford, Oxford, UK
| | - M U Kaikkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - E Aavik
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - N Laham-Karam
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - U Oppermann
- Botnar Research Centre, Oxford NIHR BRU, University of Oxford, Oxford, UK
- Oxford Centre for Translational Myeloma Research, University of Oxford, Oxford, OX3 7LD, UK
| | - J P Laakkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
| | - S Ylä-Herttuala
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
- Science Service Center, Kuopio University Hospital, Kuopio, Finland
- Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland
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4
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Rossi T, Iorio E, Chirico M, Pisanu ME, Amodio N, Cantafio MEG, Perrotta I, Colciaghi F, Fiorillo M, Gianferrari A, Puccio N, Neri A, Ciarrocchi A, Pistoni M. BET inhibitors (BETi) influence oxidative phosphorylation metabolism by affecting mitochondrial dynamics leading to alterations in apoptotic pathways in triple-negative breast cancer (TNBC) cells. Cell Prolif 2024; 57:e13730. [PMID: 39223828 PMCID: PMC11628750 DOI: 10.1111/cpr.13730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 07/04/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Repressing BET proteins' function using bromodomain inhibitors (BETi) has been shown to elicit antitumor effects by regulating the transcription of genes downstream of BRD4. We previously showed that BETi promoted cell death of triple-negative breast cancer (TNBC) cells. Here, we proved that BETi induce altered mitochondrial dynamics fitness in TNBC cells falling in cell death. We demonstrated that BETi treatment downregulated the expression of BCL-2, and proteins involved in mitochondrial fission and increased fused mitochondria. Impaired mitochondrial fission affected oxidative phosphorylation (OXPHOS) inducing the expression of OXPHOS-related genes, SDHa and ATP5a, and increased cell death. Consistently, the amount of mitochondrial DNA and mitochondrial membrane potential (∆Ψm) increased in BETi-treated cells compared to control cells. Lastly, BETi in combination with Metformin reduced cell growth. Our results indicate that mitochondrial dynamics and OXPHOS metabolism support breast cancer proliferation and represent novel BETi downstream targets in TNBC cells.
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Affiliation(s)
- Teresa Rossi
- Laboratory of Translational ResearchAUSL‐IRCCS di Reggio EmiliaReggio EmilaItaly
| | - Egidio Iorio
- High Resolution NMR UnitCore Facilities, Istituto Superiore di SanitàRomeItaly
| | - Mattea Chirico
- High Resolution NMR UnitCore Facilities, Istituto Superiore di SanitàRomeItaly
| | - Maria Elena Pisanu
- High Resolution NMR UnitCore Facilities, Istituto Superiore di SanitàRomeItaly
| | - Nicola Amodio
- Department of Experimental and Clinical MedicineUniversity Magna Graecia of CatanzaroCatanzaroItaly
| | | | - Ida Perrotta
- Department of Biology, Ecology and Earth SciencesCentre for Microscopy and Microanalysis (CM2), University of CalabriaCosenzaItaly
| | | | - Marco Fiorillo
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Alessia Gianferrari
- Laboratory of Translational ResearchAUSL‐IRCCS di Reggio EmiliaReggio EmilaItaly
| | - Noemi Puccio
- Laboratory of Translational ResearchAUSL‐IRCCS di Reggio EmiliaReggio EmilaItaly
| | - Antonino Neri
- Scientific DirectorateAUSL‐IRCCS di Reggio EmiliaReggio EmilaItaly
| | - Alessia Ciarrocchi
- Laboratory of Translational ResearchAUSL‐IRCCS di Reggio EmiliaReggio EmilaItaly
| | - Mariaelena Pistoni
- Laboratory of Translational ResearchAUSL‐IRCCS di Reggio EmiliaReggio EmilaItaly
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5
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Chandrashekar DS, Afaq F, Karthikeyan SK, Athar M, Shrestha S, Singh R, Manne U, Varambally S. Bromodomain inhibitor treatment leads to overexpression of multiple kinases in cancer cells. Neoplasia 2024; 57:101046. [PMID: 39241280 PMCID: PMC11408867 DOI: 10.1016/j.neo.2024.101046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/26/2024] [Accepted: 08/26/2024] [Indexed: 09/09/2024]
Abstract
The bromodomain and extraterminal (BET) family of proteins show altered expression across various cancers. The members of the bromodomain (BRD) family contain epigenetic reader domains that bind to acetylated lysine residues in both histone and non-histone proteins. Since BRD proteins are involved in cancer initiation and progression, therapeutic targeting of these proteins has recently been an area of interest. In experimental settings, JQ1, a commonly used BRD inhibitor, is the first known inhibitor to target BRD-containing protein 4 (BRD4), a ubiquitously expressed BRD and extraterminal family protein. BRD4 is necessary for a normal cell cycle, and its aberrant expression activates pro-inflammatory cytokines, leading to tumor initiation and progression. Various BRD4 inhibitors have been developed recently and tested in preclinical settings and are now in clinical trials. However, as with many targeted therapies, BRD inhibitor treatment can lead to resistance to treatment. Here, we investigated the kinases up-regulated on JQ1 treatment that may serve as target for combination therapy along with BRD inhibitors. To identify kinase targets, we performed a comparative analysis of gene expression data using RNA from BRD inhibitor-treated cells or BRD-modulated cells and identified overexpression of several kinases, including FYN, NEK9, and ADCK5. We further validated, by immunoblotting, the overexpression of FYN tyrosine kinase; NEK9 serine/threonine kinase and ADCK5, an atypical kinase, to confirm their overexpression after BRD inhibitor treatment. Importantly, our studies show that targeting FYN or NEK9 along with BRD inhibitor effectively reduces proliferation of cancer cells. Therefore, our research emphasizes a potential approach of utilizing inhibitors targeting some of the overexpressed kinases in conjunction with BRD inhibitors to enhance therapeutic effectiveness.
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Affiliation(s)
| | - Farrukh Afaq
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Mohammad Athar
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sadeep Shrestha
- Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA
| | | | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sooryanarayana Varambally
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL, USA.
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6
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Paterson LC, Humphreys PG, Kelly HA, Kerr WJ. Collaborative GSK-University of Strathclyde doctoral research and training programmes: Transforming approaches to industry-academia engagement. Drug Discov Today 2024; 29:104162. [PMID: 39245346 DOI: 10.1016/j.drudis.2024.104162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/23/2024] [Accepted: 09/05/2024] [Indexed: 09/10/2024]
Abstract
A global biopharma company, GSK, and the University of Strathclyde have developed an expansive and transformative research and training partnership originating in chemistry-aligned disciplines, with subsequent extensive expansion across further areas of the company. This has opened unique approaches for the delivery of collaborative research innovations while also enhancing the professional development and learning of GSK personnel, in addition to other embedded researchers and collaborating scientists, on a pathway towards more rapid and efficient discovery of new medicines.
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Affiliation(s)
- Laura C Paterson
- University of Strathclyde, Pure and Applied Chemistry, 295 Cathedral Street, Glasgow G1 1XL, UK
| | | | - Henry A Kelly
- GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
| | - William J Kerr
- University of Strathclyde, Pure and Applied Chemistry, 295 Cathedral Street, Glasgow G1 1XL, UK.
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7
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Luo Y, Chen M, Zhang T, Peng Q. 2D nanomaterials-based delivery systems and their potentials in anticancer synergistic photo-immunotherapy. Colloids Surf B Biointerfaces 2024; 242:114074. [PMID: 38972257 DOI: 10.1016/j.colsurfb.2024.114074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/22/2024] [Accepted: 07/03/2024] [Indexed: 07/09/2024]
Abstract
As the field of cancer therapeutics evolves, integrating two-dimensional (2D) nanomaterials with photo-immunotherapy has emerged as a promising approach with significant potential to augment cancer treatment efficacy. These 2D nanomaterials include graphene-based 2D nanomaterials, 2D MXenes, 2D layered double hydroxides, black phosphorus nanosheets, 2D metal-organic frameworks, and 2D transition metal dichalcogenides. They exhibit high load capacities, multiple functionalization pathways, optimal biocompatibility, and physiological stability. Predominantly, they function as anti-tumor delivery systems, amalgamating diverse therapeutic modalities, most notably phototherapy and immunotherapy, and the former is a recognized non-invasive treatment modality, and the latter represents the most promising anti-cancer strategy presently accessible. Thus, integrating phototherapy and immunotherapy founded on 2D nanomaterials unveils a novel paradigm in the war against cancer. This review delineates the latest developments in 2D nanomaterials as delivery systems for synergistic photo-immunotherapy in cancer treatment. We elaborate on the burgeoning realm of photo-immunotherapy, exploring the interplay between phototherapy and enhanced immune cells, immune response modulation, or immunosuppressive tumor microenvironments. Notably, the strategies to augment photo-immunotherapy have also been discussed. Finally, we discuss the challenges and future perspectives of these 2D nanomaterials in photo-immunotherapy.
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Affiliation(s)
- Yankun Luo
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ming Chen
- West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ting Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Qiang Peng
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
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8
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Yang Q, Falahati A, Khosh A, Lastra RR, Boyer TG, Al-Hendy A. Unraveling the Role of Bromodomain and Extra-Terminal Proteins in Human Uterine Leiomyosarcoma. Cells 2024; 13:1443. [PMID: 39273015 PMCID: PMC11394028 DOI: 10.3390/cells13171443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 08/17/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma, associated with poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is limited. Bromodomain and extra-terminal (BET) proteins are involved in both physiological and pathological events. However, the role of BET proteins in the pathogenesis of uLMS is unknown. Here, we show for the first time that BET protein family members, BRD2, BRD3, and BRD4, are aberrantly overexpressed in uLMS tissues compared to the myometrium, with a significant change by histochemical scoring assessment. Furthermore, inhibiting BET proteins with their small, potent inhibitors (JQ1 and I-BET 762) significantly inhibited the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-sequencing analysis revealed that the inhibition of BET proteins with JQ1 and I-BET 762 altered several critical pathways, including the hedgehog pathway, EMT, and transcription factor-driven pathways in uLMS. In addition, the targeted inhibition of BET proteins altered several other epigenetic regulators, including DNA methylases, histone modification, and m6A regulators. The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis. Accordingly, targeting the vulnerable epigenome may provide an additional regulatory mechanism for uterine cancer treatment.
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Affiliation(s)
- Qiwei Yang
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA;
| | - Ali Falahati
- Poundbury Cancer Institute for Personalised Medicine, Dorchester DT1 3BJ, UK;
- DNA GTx LAB, Dubai Healthcare City, Dubai 505262, United Arab Emirates
| | - Azad Khosh
- Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (A.K.); (T.G.B.)
| | - Ricardo R. Lastra
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA;
| | - Thomas G. Boyer
- Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (A.K.); (T.G.B.)
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA;
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9
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Foda MY, Salem ML, AlAkwaa FM, El-Khawaga OY. Atorvastatin lowers breast cancer risk by reversing an early tumorigenic signature. Sci Rep 2024; 14:17803. [PMID: 39090164 PMCID: PMC11294600 DOI: 10.1038/s41598-024-67706-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 07/15/2024] [Indexed: 08/04/2024] Open
Abstract
Breast cancer remains a significant health challenge with complex molecular mechanisms. While many studies have explored genetic markers in breast carcinogenesis, few have studied the potential impact of pharmacological interventions such as Atorvastatin on its genetic landscape. This study aimed to elucidate the molecular distinctions between normal and tumor-adjacent tissues in breast cancer and to investigate the potential protective role of atorvastatin, primarily known for its lipid-lowering effects, against breast cancer. Searching the Gene Expression Omnibus database identified two datasets, GSE9574 and GSE20437, comparing normal breast tissues with tumor-adjacent samples, which were merged, and one dataset, GSE63427, comparing paired pre- and post-treated patients with atorvastatin. Post-ComBat application showed merged datasets' consistency, revealing 116 DEGs between normal and tumor-adjacent tissues. Although initial GSE63427 data analysis suggested a minimal impact of atorvastatin, 105 DEGs post-treatment were discovered. Thirteen genes emerged as key players, both affected by Atorvastatin and dysregulated in tumor-adjacent tissues. Pathway analysis spotlighted the significance of these genes in processes like inflammation, oxidative stress, apoptosis, and cell cycle control. Moreover, there was a noticeable interaction between these genes and the immunological microenvironment in tumor-adjacent tissues, with Atorvastatin potentially altering the suppressive immune landscape to favor anti-tumor immunity. Survival analysis further highlighted the prognostic potential of the 13-gene panel, with 12 genes associated with improved survival outcomes. The 13-gene signature offers promising insights into breast cancer's molecular mechanisms and atorvastatin's potential therapeutic role. The preliminary findings advocate for an in-depth exploration of atorvastatin's impact on.
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Affiliation(s)
- Mohamed Y Foda
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt
| | - Mohamed L Salem
- Immunology and Biotechnology Unit, Department of Zoology, Faculty of Science, and Center of Excellence in Cancer Research, Tanta University, Tanta, Egypt
| | - Fadhl M AlAkwaa
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Omali Y El-Khawaga
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt.
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10
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Song Q, Wang A, Zhang Y, Zhu J, Wang X, Wang J, Shi H. A transformable and self-oxygenated smart probe for enhanced tumor sonodynamic therapy. Acta Biomater 2024; 184:409-418. [PMID: 38908418 DOI: 10.1016/j.actbio.2024.06.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 06/09/2024] [Accepted: 06/13/2024] [Indexed: 06/24/2024]
Abstract
Sonodynamic therapy (SDT) is emerging as a promising modality for cancer treatment. However, improving the tumor bioavailability and anti-hypoxia capability of sonosensitizers faces a big challenge. In this work, we present a tumor microenvironment (TME)-mediated nanomorphology transformation and oxygen (O2) self-production strategy to enhance the sonodynamic therapeutic efficacy of tumors. A smart probe Ce6-Leu@Mn2+ that consists of a glutathione (GSH) and leucine amino peptidase (LAP) dual-responsive unit, a 2-cyanobenzothiazole (CBT) group, and a Mn2+-chelated Ce6 as sonosensitizer for tumor SDT was synthesized, and its SDT potential for liver tumor HepG2 in living mice was systematically studied. It was found that the probes could self-assemble into large nanoparticles in physiological condition and spontaneously transformed into small particles under the dual stimulation of GSH and LAP in TME resulting in enhanced tumor accumulation and deep penetration. More notably, Ce6-Leu@Mn2+ could convert endogenous hydrogen peroxide to O2, thereby alleviating the hypoxia and achieving effective SDT against hypoxic tumors under the excitation of ultrasound. We thus believe this smart TME-responsive probe may provide a noninvasive and efficient means for malignant tumor treatment. STATEMENT OF SIGNIFICANCE: Sonodynamic therapy (SDT) is emerging as a promising therapeutic modality for cancer treatment. However, how to improve the tumor bioavailability and anti-hypoxia capability of sonosensitizers remains a huge challenge. Herein, we rationally developed a theranostic probe Ce6-Leu@Mn2+ that can transform into small-size nanoparticles from initial large particles under the dual stimulation of LAP and GSH in tumor microenvironment (TME) resulting in enhanced tumor accumulation, deep tissue penetration as well as remarkable O2 self-production for enhanced sonodynamic therapy of human liver HepG2 tumor in living mice. This smart TME-responsive probe may provide a noninvasive and efficient means for hypoxic tumor treatment.
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Affiliation(s)
- Qingfei Song
- Department of Ultrasound, First Hospital of Shanxi Medical University, 85 Jiefang Nan Road, Taiyuan, Shanxi 030001, China; Department of Ultrasound, Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, China
| | - Anna Wang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Yuqi Zhang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Jinfeng Zhu
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Roma, Italy
| | - Xiaoyan Wang
- Department of Ultrasound, Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, China.
| | - Jian Wang
- Department of Ultrasound, First Hospital of Shanxi Medical University, 85 Jiefang Nan Road, Taiyuan, Shanxi 030001, China.
| | - Haibin Shi
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
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11
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Trnkova L, Buocikova V, Mego M, Cumova A, Burikova M, Bohac M, Miklikova S, Cihova M, Smolkova B. Epigenetic deregulation in breast cancer microenvironment: Implications for tumor progression and therapeutic strategies. Biomed Pharmacother 2024; 174:116559. [PMID: 38603889 DOI: 10.1016/j.biopha.2024.116559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/27/2024] [Accepted: 04/04/2024] [Indexed: 04/13/2024] Open
Abstract
Breast cancer comprises a substantial proportion of cancer diagnoses in women and is a primary cause of cancer-related mortality. While hormone-responsive cases generally have a favorable prognosis, the aggressive nature of triple-negative breast cancer presents challenges, with intrinsic resistance to established treatments being a persistent issue. The complexity intensifies with the emergence of acquired resistance, further complicating the management of breast cancer. Epigenetic changes, encompassing DNA methylation, histone and RNA modifications, and non-coding RNAs, are acknowledged as crucial contributors to the heterogeneity of breast cancer. The unique epigenetic landscape harbored by each cellular component within the tumor microenvironment (TME) adds great diversity to the intricate regulations which influence therapeutic responses. The TME, a sophisticated ecosystem of cellular and non-cellular elements interacting with tumor cells, establishes an immunosuppressive microenvironment and fuels processes such as tumor growth, angiogenesis, and extracellular matrix remodeling. These factors contribute to challenging conditions in cancer treatment by fostering a hypoxic environment, inducing metabolic stress, and creating physical barriers to drug delivery. This article delves into the complex connections between breast cancer treatment response, underlying epigenetic changes, and vital interactions within the TME. To restore sensitivity to treatment, it emphasizes the need for combination therapies considering epigenetic changes specific to individual members of the TME. Recognizing the pivotal role of epigenetics in drug resistance and comprehending the specificities of breast TME is essential for devising more effective therapeutic strategies. The development of reliable biomarkers for patient stratification will facilitate tailored and precise treatment approaches.
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Affiliation(s)
- Lenka Trnkova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 845 05, Slovakia
| | - Verona Buocikova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 845 05, Slovakia
| | - Michal Mego
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 845 05, Slovakia; 2nd Department of Oncology, Comenius University, Faculty of Medicine & National Cancer Institute, Bratislava 83310, Slovakia
| | - Andrea Cumova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 845 05, Slovakia
| | - Monika Burikova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 845 05, Slovakia
| | - Martin Bohac
- 2nd Department of Oncology, Comenius University, Faculty of Medicine & National Cancer Institute, Bratislava 83310, Slovakia; Regenmed Ltd., Medena 29, Bratislava 811 01, Slovakia; Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava 811 08, Slovakia
| | - Svetlana Miklikova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 845 05, Slovakia
| | - Marina Cihova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 845 05, Slovakia
| | - Bozena Smolkova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 845 05, Slovakia.
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12
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Soliman SHA, Iwanaszko M, Zheng B, Gold S, Howard BC, Das M, Chakrabarty RP, Chandel NS, Shilatifard A. Transcriptional elongation control of hypoxic response. Proc Natl Acad Sci U S A 2024; 121:e2321502121. [PMID: 38564636 PMCID: PMC11009653 DOI: 10.1073/pnas.2321502121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 02/23/2024] [Indexed: 04/04/2024] Open
Abstract
The release of paused RNA polymerase II (RNAPII) from promoter-proximal regions is tightly controlled to ensure proper regulation of gene expression. The elongation factor PTEF-b is known to release paused RNAPII via phosphorylation of the RNAPII C-terminal domain by its cyclin-dependent kinase component, CDK9. However, the signal and stress-specific roles of the various RNAPII-associated macromolecular complexes containing PTEF-b/CDK9 are not yet clear. Here, we identify and characterize the CDK9 complex required for transcriptional response to hypoxia. Contrary to previous reports, our data indicate that a CDK9 complex containing BRD4 but not AFF1/4 is essential for this hypoxic stress response. We demonstrate that BRD4 bromodomains (BET) are dispensable for the release of paused RNAPII at hypoxia-activated genes and that BET inhibition by JQ1 is insufficient to impair hypoxic gene response. Mechanistically, we demonstrate that the C-terminal region of BRD4 is required for Polymerase-Associated Factor-1 Complex (PAF1C) recruitment to establish an elongation-competent RNAPII complex at hypoxia-responsive genes. PAF1C disruption using a small-molecule inhibitor (iPAF1C) impairs hypoxia-induced, BRD4-mediated RNAPII release. Together, our results provide insight into potentially targetable mechanisms that control the hypoxia-responsive transcriptional elongation.
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Affiliation(s)
- Shimaa Hassan AbdelAziz Soliman
- Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Marta Iwanaszko
- Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Bin Zheng
- Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Sarah Gold
- Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Benjamin Charles Howard
- Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Madhurima Das
- Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
| | - Ram Prosad Chakrabarty
- Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
- Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University, Chicago, IL60611
| | - Navdeep S. Chandel
- Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
- Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University, Chicago, IL60611
| | - Ali Shilatifard
- Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL60611
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13
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Papadimitropoulou A, Makri M, Zoidis G. MYC the oncogene from hell: Novel opportunities for cancer therapy. Eur J Med Chem 2024; 267:116194. [PMID: 38340508 DOI: 10.1016/j.ejmech.2024.116194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024]
Abstract
Cancer comprises a heterogeneous disease, characterized by diverse features such as constitutive expression of oncogenes and/or downregulation of tumor suppressor genes. MYC constitutes a master transcriptional regulator, involved in many cellular functions and is aberrantly expressed in more than 70 % of human cancers. The Myc protein belongs to a family of transcription factors whose structural pattern is referred to as basic helix-loop-helix-leucine zipper. Myc binds to its partner, a smaller protein called Max, forming an Myc:Max heterodimeric complex that interacts with specific DNA recognition sequences (E-boxes) and regulates the expression of downstream target genes. Myc protein plays a fundamental role for the life of a cell, as it is involved in many physiological functions such as proliferation, growth and development since it controls the expression of a very large percentage of genes (∼15 %). However, despite the strict control of MYC expression in normal cells, MYC is often deregulated in cancer, exhibiting a key role in stimulating oncogenic process affecting features such as aberrant proliferation, differentiation, angiogenesis, genomic instability and oncogenic transformation. In this review we aim to meticulously describe the fundamental role of MYC in tumorigenesis and highlight its importance as an anticancer drug target. We focus mainly on the different categories of novel small molecules that act as inhibitors of Myc function in diverse ways hence offering great opportunities for an efficient cancer therapy. This knowledge will provide significant information for the development of novel Myc inhibitors and assist to the design of treatments that would effectively act against Myc-dependent cancers.
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Affiliation(s)
- Adriana Papadimitropoulou
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece
| | - Maria Makri
- Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771, Athens, Greece
| | - Grigoris Zoidis
- Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771, Athens, Greece.
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14
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Guefack MGF, Bhatnagar S. Advances in Epigenetic Therapeutics for Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1465:89-97. [PMID: 39586995 DOI: 10.1007/978-3-031-66686-5_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
The epigenetic deregulations correlate with tumorigenesis, resistance to therapy, and metastasis of breast cancer cells. Given the predominance of aberrant epigenomic mechanisms, there is a growing emphasis on targeting epigenetic mechanisms for breast cancer therapeutic development. Selective inhibitors of epigenetic enzymes and the combined approach of epigenetic therapies with chemotherapies or hormone therapies in the treatment of breast cancer represent promising therapeutic strategies. In this chapter, we review the targeting of epigenetic mechanisms and highlight current epigenetic research in the development of breast cancer therapy.
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Affiliation(s)
- Michel-Gael F Guefack
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, USA
| | - Sanchita Bhatnagar
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, USA.
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15
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Hu H, Tjaden A, Knapp S, Antolin AA, Müller S. A machine learning and live-cell imaging tool kit uncovers small molecules induced phospholipidosis. Cell Chem Biol 2023; 30:1634-1651.e6. [PMID: 37797617 DOI: 10.1016/j.chembiol.2023.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 08/09/2023] [Accepted: 09/14/2023] [Indexed: 10/07/2023]
Abstract
Drug-induced phospholipidosis (DIPL), characterized by excessive accumulation of phospholipids in lysosomes, can lead to clinical adverse effects. It may also alter phenotypic responses in functional studies using chemical probes. Therefore, robust methods are needed to predict and quantify phospholipidosis (PL) early in drug discovery and in chemical probe characterization. Here, we present a versatile high-content live-cell imaging approach, which was used to evaluate a chemogenomic and a lysosomal modulation library. We trained and evaluated several machine learning models using the most comprehensive set of publicly available compounds and interpreted the best model using SHapley Additive exPlanations (SHAP). Analysis of high-quality chemical probes extracted from the Chemical Probes Portal using our algorithm revealed that closely related molecules, such as chemical probes and their matched negative controls can differ in their ability to induce PL, highlighting the importance of identifying PL for robust target validation in chemical biology.
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Affiliation(s)
- Huabin Hu
- Centre for Cancer Drug Discovery, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK; Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, SE-751 24 Uppsala, Sweden
| | - Amelie Tjaden
- Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, 60438 Frankfurt am Main, Germany; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, 60438 Frankfurt am Main, Germany
| | - Stefan Knapp
- Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, 60438 Frankfurt am Main, Germany; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, 60438 Frankfurt am Main, Germany
| | - Albert A Antolin
- Centre for Cancer Drug Discovery, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia Barcelona, Spain.
| | - Susanne Müller
- Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, 60438 Frankfurt am Main, Germany; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, 60438 Frankfurt am Main, Germany.
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16
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Talukdar PD, Chatterji U. Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases. Signal Transduct Target Ther 2023; 8:427. [PMID: 37953273 PMCID: PMC10641101 DOI: 10.1038/s41392-023-01651-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/27/2023] [Accepted: 09/10/2023] [Indexed: 11/14/2023] Open
Abstract
Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and the co-activators. Deregulation of these regulatory molecules is associated with cell state transitions, which in turn is accountable for diverse maladies, including developmental disorders, metabolic disorders, and most significantly, cancer. A decade back most transcription factors, the key enablers of disease development, were historically viewed as 'undruggable'; however, in the intervening years, a wealth of literature validated that they can be targeted indirectly through transcriptional co-activators, their confederates in various physiological and molecular processes. These co-activators, along with transcription factors, have the ability to initiate and modulate transcription of diverse genes necessary for normal physiological functions, whereby, deregulation of such interactions may foster tissue-specific disease phenotype. Hence, it is essential to analyze how these co-activators modulate specific multilateral processes in coordination with other factors. The proposed review attempts to elaborate an in-depth account of the transcription co-activators, their involvement in transcription regulation, and context-specific contributions to pathophysiological conditions. This review also addresses an issue that has not been dealt with in a comprehensive manner and hopes to direct attention towards future research that will encompass patient-friendly therapeutic strategies, where drugs targeting co-activators will have enhanced benefits and reduced side effects. Additional insights into currently available therapeutic interventions and the associated constraints will eventually reveal multitudes of advanced therapeutic targets aiming for disease amelioration and good patient prognosis.
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Affiliation(s)
- Priyanka Dey Talukdar
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, West Bengal, India
| | - Urmi Chatterji
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, West Bengal, India.
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17
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Kim J, Kim S, Park SY, Lee GK, Lim KY, Kim JY, Hwang JA, Yu N, Kang EH, Hwang M, Song BR, Park C, Han JY. Molecular Subtypes and Tumor Microenvironment Characteristics of Small-Cell Lung Cancer Associated with Platinum-Resistance. Cancers (Basel) 2023; 15:3568. [PMID: 37509231 PMCID: PMC10377352 DOI: 10.3390/cancers15143568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/30/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Although molecular subtypes of small-cell lung cancer (SCLC) have been proposed, their clinical relevance and therapeutic implications are not fully understood. Thus, we aimed to refine molecular subtypes and to uncover therapeutic targets. We classified the subtypes based on gene expression (n = 81) and validated them in our samples (n = 87). Non-SCLC samples were compared with SCLC subtypes to identify the early development stage of SCLC. Single-cell transcriptome analysis was applied to dissect the TME of bulk samples. Finally, to overcome platinum resistance, we performed drug screening of patient-derived cells and cell lines. Four subtypes were identified: the ASCL1+ (SCLC-A) subtype identified as TP53/RB-mutated non-SCLC representing the early development stage of SCLC; the immune activation (SCLC-I) subtype, showing high CD8+/PD-L1+ T-cell infiltration and endothelial-to-mesenchymal transition (EndMT); the NEUROD1 (SCLC-N) subtype, which showed neurotransmission process; and the POU2F3+ (SCLC-P) subtype with epithelial-to-mesenchymal transition (EMT). EndMT was associated with the worst prognosis. While SCLC-A/N exhibited platinum sensitivity, the EndMT signal of SCLC-I conferred platinum resistance. A BET inhibitor suppressed the aggressive angiogenesis phenotype of SCLC-I. We revealed that EndMT development contributed to a poor outcome in SCLC-I. Moreover, heterogenous TME development facilitated platinum resistance. BET inhibitors are novel candidates for overcoming platinum resistance.
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Affiliation(s)
- Jihyun Kim
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
- Korea Disease Control and Prevention Agency, Osong Health Technology Administration Complex, 187, Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si 28159, Chungcheongbuk-do, Republic of Korea
| | - Sunshin Kim
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Seog-Yun Park
- Department of Pathology, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Geon Kook Lee
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Kun Young Lim
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Jin Young Kim
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Jung-Ah Hwang
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Namhee Yu
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Eun Hye Kang
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Mihwa Hwang
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Bo Ram Song
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Charny Park
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
| | - Ji-Youn Han
- Research Institute, National Cancer Center, 232 Ilsan-ro, Goyang-si 10408, Kyeonggi-do, Republic of Korea
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18
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Deng H, Wang G, Zhao S, Tao Y, Zhang Z, Yang J, Lei Y. New hope for tumor immunotherapy: the macrophage-related "do not eat me" signaling pathway. Front Pharmacol 2023; 14:1228962. [PMID: 37484024 PMCID: PMC10358856 DOI: 10.3389/fphar.2023.1228962] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
The "do not eat me" signaling pathway is extremely active in tumor cells, providing a means for these cells to elude macrophage phagocytosis and escape immune surveillance. Representative markers of this pathway, such as CD47 and CD24, are highly expressed in numerous tumors. The interaction of SIRPα with CD47 reduces the accumulation of non-myosin ⅡA on the cell membrane. The combination of CD24 and Siglec10 ultimately leads to the recruitment of SHP-1 or SHP-2 to reduce signal transduction. Both of them weaken the ability of macrophages to engulf tumor cells. Blocking the mutual recognition between CD47-SIRPα or CD24-Siglec10 using large molecular proteins or small molecular drugs represents a promising avenue for tumor immunotherapy. Doing so can inhibit signal transduction and enhance macrophage clearance rates of cancer cells. In this paper, we summarize the characteristics of the drugs that affect the "do not eat me" signaling pathway via classical large molecular proteins and small molecule drugs, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways, which target the CD47-SIRPα and CD24-Siglec10 signaling pathways. We expect it will offer insight into the development of new drugs centered on blocking the "do not eat me" signaling pathway.
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Affiliation(s)
- Han Deng
- General Practice Ward/International Medical Center, General Practice Medical Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Guan Wang
- General Practice Ward/International Medical Center, General Practice Medical Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Shengyan Zhao
- General Practice Ward/International Medical Center, General Practice Medical Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Yiran Tao
- West China-California Research Center for Predictive Intervention Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhixiong Zhang
- General Practice Ward/International Medical Center, General Practice Medical Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Jinliang Yang
- General Practice Ward/International Medical Center, General Practice Medical Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Yi Lei
- General Practice Ward/International Medical Center, General Practice Medical Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
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19
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Bioinformatic Analysis of Human Cumulus Cells to Unravel Cellular's Processes that Could Be Used to Establish Oocyte Quality Biomarkers with Clinical Application. Reprod Sci 2023; 30:642-655. [PMID: 35882717 DOI: 10.1007/s43032-022-01046-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 07/18/2022] [Indexed: 10/16/2022]
Abstract
Metadata analysis of public microarray datasets using bioinformatics tools has been successfully used in several biomedical fields in the search for biomarkers. In reproductive science, there is an urgent need for the establishment of oocyte quality biomarkers that could be used in the clinical environment to increase the chances of successful outcomes in treatment cycles. Adaptive cellular processes observed in cumulus oophorus cells reflect the conditions of the follicular microenvironment and may thus bring relevant information of oocyte's conditions. Here we analyzed human cumulus cells gene expression datasets in search of predictors of oocyte quality, a strategy which uncovered several cellular processes positively and negatively associated with embryo development and pregnancy potential. Secondly, the expression levels of genes that were present in the majority of processes observed were validated in house with clinical samples. Our data confirmed the association of the selected biomarkers with blastocyst formation and pregnancy potential rates, independently of patients' clinical characteristics such as diagnosis, age, BMI, and stimulation protocol applied. This study shows that bioinformatic analysis of cellular processes can be successfully used to elucidate possible oocyte quality biomarkers. Our data reinforces the need to consider clinical characteristics of patients when selecting relevant biomarkers to be used in the clinical environment and suggests a combination of positive (PTGS2) and negative (CYPB1) quality biomarkers as a robust strategy for a complementary oocyte selection tool, potentially increasing assisted reproduction success rates. Also, GPX4 expression as pregnancy potential biomarker is indicated here as a possibility for further investigations.
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20
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Qin M, Liu Q, Yang W, Wang Q, Xiang Z. IGFL2‐AS1
‐induced suppression of
HIF
‐1α degradation promotes cell proliferation and invasion in colorectal cancer by upregulating
CA9. Cancer Med 2022; 12:8415-8432. [PMID: 36537608 PMCID: PMC10134350 DOI: 10.1002/cam4.5562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/14/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
PURPOSE The lncRNA IGFL2-AS1 is a known cancer-promoting factor in colorectal cancer (CRC); nonetheless, the mechanism of its carcinogenic effects has not yet been elucidated. This study elaborated on the role and underlying molecular mechanism of IGFL2-AS1 in promoting CRC cell functions. METHODS IGLF2-AS1 expression levels in CRC tissue/normal tissue and CRC cell line/normal colon epithelial cell line were detected by quantitative real-time polymerase chain reaction. Cell counting kit-8, colony formation assay, and EdU assay were performed to assess the effect of IGFL2-AS1 knockdown or overexpression on the proliferative capacity of CRC cells. The migration and invasion abilities of LoVo cells were measured using transwell assay. The expression relationship between IGFL2-AS1 and carbonic anhydrase 9 (CA9) and the CA9 expression level in CRC tissues and cells was verified by transcriptome sequencing, western blotting, and immunohistochemical staining. Treatment with MG132 and cycloheximide was utilized to explore the mechanism by which IGFL2-AS1 affects the hypoxia-inducible factor-1α (HIF-1α)/CA9 pathway. A nude mouse xenograft model was constructed to evaluate the effect of IGFL2-AS1 on CRC growth in vivo. RESULTS We discovered that IGFL2-AS1 was highly upregulated in CRC tumor tissues and cells. IGFL2-AS1 can functionally promote CRC cell proliferation, migration, and invasion in vitro and accelerate CRC occurrence in vivo. Mechanistic studies demonstrated that IGFL2-AS1 upregulated the CA9 level by affecting the degradation pathway of HIF-1α, which elucidates its pro-proliferative effect in CRC. The lncRNA IGFL2-AS1 mediated the inhibition of HIF-1α degradation in CRC and increased CA9 expression, thereby promoting CRC progression. CONCLUSION Our findings suggested that IGFL2-AS1 is expected to be a promising new diagnostic marker and therapeutic target for CRC.
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Affiliation(s)
- Mengdi Qin
- Department of Gastrointestinal Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing China
- Chongqing Key Laboratory of Department of General Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing China
| | - Qiang Liu
- Department of Gastrointestinal Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing China
- Chongqing Key Laboratory of Department of General Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing China
| | - Wei Yang
- Department of Gastrointestinal Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing China
| | - Qiaofeng Wang
- Department of Gastrointestinal Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing China
| | - Zheng Xiang
- Department of Gastrointestinal Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing China
- Chongqing Key Laboratory of Department of General Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing China
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21
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Do TC, Lau JW, Sun C, Liu S, Kha KT, Lim ST, Oon YY, Kwan YP, Ma JJ, Mu Y, Liu X, Carney TJ, Wang X, Xing B. Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras. SCIENCE ADVANCES 2022; 8:eabq2216. [PMID: 36516252 PMCID: PMC9750146 DOI: 10.1126/sciadv.abq2216] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 11/12/2022] [Indexed: 06/17/2023]
Abstract
Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective therapeutics. Unfortunately, precise and microenvironment-activatable BET protein degradation content with promising tumor selectivity and pharmacological suitability remains elusive. Here, we present an enzyme-derived clicking PROTACs (ENCTACs) capable of orthogonally cross-linking two disparate small-molecule warhead ligands that recognize BET bromodomain-containing protein 4 (BRD4) protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme. This localized formation of heterobifunctional degraders promotes specific down-regulation of BRD4, which subsequently alters expression of epigenetic targets and, therefore, allows precise modulation of hypoxic signaling in live cells, zebrafish, and living mice with solid tumors. Our activation-feedback system demonstrates compelling superiorities and may enable the PROTAC technology with more flexible practicality and druggable potency for precision medicine in the near future.
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Affiliation(s)
- Thang Cong Do
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
| | - Jun Wei Lau
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
- Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
| | - Caixia Sun
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
| | - Songhan Liu
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
| | - Khoa Tuan Kha
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
| | - Seok Ting Lim
- Duke-NUS Medical School, Singapore 169857, Singapore
- Singapore Eye Research Institute, Singapore 169856, Singapore
| | - Yu Yang Oon
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| | - Yuet Ping Kwan
- Duke-NUS Medical School, Singapore 169857, Singapore
- Singapore Eye Research Institute, Singapore 169856, Singapore
| | - Jia Jia Ma
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore
| | - Yuguang Mu
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| | - Xiaogang Liu
- Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
| | - Thomas James Carney
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore
| | - Xiaomeng Wang
- Duke-NUS Medical School, Singapore 169857, Singapore
- Singapore Eye Research Institute, Singapore 169856, Singapore
- Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore
| | - Bengang Xing
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637371, Singapore
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22
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Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression. Int J Mol Sci 2022; 23:ijms232315163. [PMID: 36499487 PMCID: PMC9738555 DOI: 10.3390/ijms232315163] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/25/2022] [Accepted: 11/30/2022] [Indexed: 12/03/2022] Open
Abstract
TP53 is the most common mutated gene in human cancer. Mutant p53 protein loses its tumor-suppressor properties and gains oncogenic activity. Mutant p53 is a therapeutic target in a broad range of cancer types. However, how mutant p53 is epigenetically regulated during tumor progression remains elusive. In this study, we found that the upregulation of mutant p53 is mediated by bromodomain protein BRD4 in triple-negative breast cancer (TNBC) cells. Inhibition of BRD4 with its inhibitor JQ1 or knockdown of BRD4 suppressed the transcription of mutant p53, which led to the re-expression of p21, the inhibition of S-phase entry, and colony formation in TNBC cells. BRD4 also positively regulated the transcription of wild-type p53, whereas JQ1 treatment and knockdown of BRD4 decreased the expression of p21 in MCF-7 cells. Knockdown of BRD4 resulted in attenuation of TNBC tumor growth in vivo. Taken together, our results uncover a novel regulatory mechanism of mutant p53 via BRD4, and suggest that the bromodomain inhibitor suppresses tumorigenesis through targeting mutant p53 in TNBC.
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23
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The BET Protein Inhibitor JQ1 Decreases Hypoxia and Improves the Therapeutic Benefit of Anti-PD-1 in a High-Risk Neuroblastoma Mouse Model. Cells 2022; 11:cells11182783. [PMID: 36139358 PMCID: PMC9497090 DOI: 10.3390/cells11182783] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
Anti-programmed death 1 (PD-1) is a revolutionary treatment for many cancers. The response to anti-PD-1 relies on several properties of tumor and immune cells, including the expression of PD-L1 and PD-1. Despite the impressive clinical benefit achieved with anti-PD-1 in several cancers in adults, the use of this therapy for high-risk neuroblastoma remains modest. Here, we evaluated the therapeutic benefit of anti-PD-1 in combination with JQ1 in a highly relevant TH-MYCN neuroblastoma transgenic mouse model. JQ1 is a small molecule inhibitor of the extra-terminal domain (BET) family of bromodomain proteins, competitively binding to bromodomains. Using several neuroblastoma cell lines in vitro, we showed that JQ1 inhibited hypoxia-dependent induction of HIF-1α and decreased the expression of the well-known HIF-1α downstream target gene CA9. Using MRI relaxometry performed on TH-MYCN tumor-bearing mice, we showed that JQ1 decreases R2* in tumors, a parameter associated with intra-tumor hypoxia in pre-clinical settings. Decreasing hypoxia by JQ1 was associated with improved blood vessel quality and integrity, as revealed by CD31 and αSMA staining on tumor sections. By analyzing the immune landscape of TH-MYCN tumors in mice, we found that JQ1 had no major impact on infiltrating immune cells into the tumor microenvironment but significantly increased the percentage of CD8+ PD-1+, conventional CD4+ PD-1+, and Treg PD-1+ cells. While anti-PD-1 monotherapy did not affect TH-MYCN tumor growth, we showed that combinatorial therapy associating JQ1 significantly decreased the tumor volume and improved the therapeutic benefit of anti-PD-1. This study provided the pre-clinical proof of concept needed to establish a new combination immunotherapy approach that may create tremendous enthusiasm for treating high-risk childhood neuroblastoma.
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24
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Jinna N, Rida P, Smart M, LaBarge M, Jovanovic-Talisman T, Natarajan R, Seewaldt V. Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer. Int J Mol Sci 2022; 23:ijms23168844. [PMID: 36012111 PMCID: PMC9408190 DOI: 10.3390/ijms23168844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/03/2022] [Accepted: 08/06/2022] [Indexed: 12/27/2022] Open
Abstract
Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes.
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Affiliation(s)
- Nikita Jinna
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | | | - Max Smart
- Rowland Hall, Salt Lake City, UT 84102, USA
| | - Mark LaBarge
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | | | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Victoria Seewaldt
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
- Correspondence:
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25
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Morphometrical, Morphological, and Immunocytochemical Characterization of a Tool for Cytotoxicity Research: 3D Cultures of Breast Cell Lines Grown in Ultra-Low Attachment Plates. TOXICS 2022; 10:toxics10080415. [PMID: 35893848 PMCID: PMC9394479 DOI: 10.3390/toxics10080415] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/15/2022] [Accepted: 07/20/2022] [Indexed: 02/06/2023]
Abstract
Three-dimensional cell cultures may better mimic avascular tumors. Yet, they still lack characterization and standardization. Therefore, this study aimed to (a) generate multicellular aggregates (MCAs) of four breast cell lines: MCF7, MDA-MB-231, and SKBR3 (tumoral) and MCF12A (non-tumoral) using ultra-low attachment (ULA) plates, (b) detail the methodology used for their formation and analysis, providing technical tips, and (c) characterize the MCAs using morphometry, qualitative cytology (at light and electron microscopy), and quantitative immunocytochemistry (ICC) analysis. Each cell line generated uniform MCAs with structural differences among cell lines: MCF7 and MDA-MB-231 MCAs showed an ellipsoid/discoid shape and compact structure, while MCF12A and SKBR3 MCAs were loose, more flattened, and presented bigger areas. MCF7 MCAs revealed glandular breast differentiation features. ICC showed a random distribution of the proliferating and apoptotic cells throughout the MCAs, not fitting in the traditional spheroid model. ICC for cytokeratin, vimentin, and E-cadherin showed different results according to the cell lines. Estrogen (ER) and progesterone (PR) receptors were positive only in MCF7 and human epidermal growth factor receptor 2 (HER-2) in SKBR3. The presented characterization of the MCAs in non-exposed conditions provided a good baseline to evaluate the cytotoxic effects of potential anticancer compounds.
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26
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De Francesco EM, Cirillo F, Vella V, Belfiore A, Maggiolini M, Lappano R. Triple-negative breast cancer drug resistance, durable efficacy, and cure: How advanced biological insights and emerging drug modalities could transform progress. Expert Opin Ther Targets 2022; 26:513-535. [PMID: 35761781 DOI: 10.1080/14728222.2022.2094762] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by the lack of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) and often associated with poor survival outcomes. The backbone of current treatments for TNBC relies on chemotherapy; however, resistance to cytotoxic agents is a commonly encountered hurdle to overcome. AREAS COVERED : Current understanding on the mechanisms involved in TNBC chemoresistance is evaluated and novel potential actionable targets and recently explored modalities for carrying and delivering chemotherapeutics are highlighted. EXPERT OPINION : A comprehensive identification of both genomic and functional TNBC signatures is required for a more definite categorization of the patients in order to prevent insensitivity to chemotherapy and therefore realize the full potential of precision-medicine approaches. In this scenario, cell-line-derived xenografts (CDX), patient-derived xenografts (PDX), patient-derived orthotopic xenografts (PDOX) and patient-derived organoids (PDO) are indispensable experimental models for evaluating the efficacy of drug candidates and predicting the therapeutic response. The combination of increasingly sensitive "omics" technologies, computational algorithms and innovative drug modalities may accelerate the successful translation of novel candidate TNBC targets from basic research to clinical settings, thus contributing to reach optimal clinical output, with lower side effects and reduced resistance.
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Affiliation(s)
- Ernestina Marianna De Francesco
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
| | - Francesca Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Veronica Vella
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
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27
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Yellapu NK, Ly T, Sardiu ME, Pei D, Welch DR, Thompson JA, Koestler DC. Synergistic anti-proliferative activity of JQ1 and GSK2801 in triple-negative breast cancer. BMC Cancer 2022; 22:627. [PMID: 35672711 PMCID: PMC9173973 DOI: 10.1186/s12885-022-09690-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 05/23/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) constitutes 10-20% of breast cancers and is challenging to treat due to a lack of effective targeted therapies. Previous studies in TNBC cell lines showed in vitro growth inhibition when JQ1 or GSK2801 were administered alone, and enhanced activity when co-administered. Given their respective mechanisms of actions, we hypothesized the combinatorial effect could be due to the target genes affected. Hence the target genes were characterized for their expression in the TNBC cell lines to prove the combinatorial effect of JQ1 and GSK2801. METHODS RNASeq data sets of TNBC cell lines (MDA-MB-231, HCC-1806 and SUM-159) were analyzed to identify the differentially expressed genes in single and combined treatments. The topmost downregulated genes were characterized for their downregulated expression in the TNBC cell lines treated with JQ1 and GSK2801 under different dose concentrations and combinations. The optimal lethal doses were determined by cytotoxicity assays. The inhibitory activity of the drugs was further characterized by molecular modelling studies. RESULTS Global expression profiling of TNBC cell lines using RNASeq revealed different expression patterns when JQ1 and GSK2801 were co-administered. Functional enrichment analyses identified several metabolic pathways (i.e., systemic lupus erythematosus, PI3K-Akt, TNF, JAK-STAT, IL-17, MAPK, Rap1 and signaling pathways) enriched with upregulated and downregulated genes when combined JQ1 and GSK2801 treatment was administered. RNASeq identified downregulation of PTPRC, MUC19, RNA5-8S5, KCNB1, RMRP, KISS1 and TAGLN (validated by RT-qPCR) and upregulation of GPR146, SCARA5, HIST2H4A, CDRT4, AQP3, MSH5-SAPCD1, SENP3-EIF4A1, CTAGE4 and RNASEK-C17orf49 when cells received both drugs. In addition to differential gene regulation, molecular modelling predicted binding of JQ1 and GSK2801 with PTPRC, MUC19, KCNB1, TAGLN and KISS1 proteins, adding another mechanism by which JQ1 and GSK2801 could elicit changes in metabolism and proliferation. CONCLUSION JQ1-GSK2801 synergistically inhibits proliferation and results in selective gene regulation. Besides suggesting that combinatorial use could be useful therapeutics for the treatment of TNBC, the findings provide a glimpse into potential mechanisms of action for this combination therapy approach.
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Affiliation(s)
- Nanda Kumar Yellapu
- Department of Biostatistics & Data Science, University of Kansas, Medical Center, KS, Kansas City, USA
- The University of Kansas Cancer Center, Kansas City, KS, USA
| | - Thuc Ly
- The University of Kansas Cancer Center, Kansas City, KS, USA
- Department of Cancer Biology, University of Kansas, Medical Center, KS, Kansas City, USA
| | - Mihaela E Sardiu
- Department of Biostatistics & Data Science, University of Kansas, Medical Center, KS, Kansas City, USA
- The University of Kansas Cancer Center, Kansas City, KS, USA
| | - Dong Pei
- Department of Biostatistics & Data Science, University of Kansas, Medical Center, KS, Kansas City, USA
- The University of Kansas Cancer Center, Kansas City, KS, USA
| | - Danny R Welch
- The University of Kansas Cancer Center, Kansas City, KS, USA
- Department of Cancer Biology, University of Kansas, Medical Center, KS, Kansas City, USA
- Departments of Molecular & Integrative Physiology and Internal Medicine, University of Kansas, Medical Center, KS, Kansas City, USA
| | - Jeffery A Thompson
- Department of Biostatistics & Data Science, University of Kansas, Medical Center, KS, Kansas City, USA.
- The University of Kansas Cancer Center, Kansas City, KS, USA.
| | - Devin C Koestler
- Department of Biostatistics & Data Science, University of Kansas, Medical Center, KS, Kansas City, USA.
- The University of Kansas Cancer Center, Kansas City, KS, USA.
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28
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The Immunological Contribution of a Novel Metabolism-Related Signature to the Prognosis and Anti-Tumor Immunity in Cervical Cancer. Cancers (Basel) 2022; 14:cancers14102399. [PMID: 35626004 PMCID: PMC9139200 DOI: 10.3390/cancers14102399] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/07/2022] [Accepted: 05/09/2022] [Indexed: 02/04/2023] Open
Abstract
Cervical cancer is the most frequently diagnosed malignancy in the female reproductive system. Conventional stratification of patients based on clinicopathological characters has gradually been outpaced by a molecular profiling strategy. Our study aimed to identify a reliable metabolism-related predictive signature for the prognosis and anti-tumor immunity in cervical cancer. In this study, we extracted five metabolism-related hub genes, including ALOX12B, CA9, FAR2, F5 and TDO2, for the establishment of the risk score model. The Kaplan-Meier curve suggested that patients with a high-risk score apparently had a worse prognosis in the cervical cancer training cohort (TCGA, n = 304, p < 0.0001), validation cohort (GSE44001, n = 300, p = 0.0059) and pan-cancer cohorts (including nine TCGA tumors). Using a gene set enrichment analysis (GSEA), we observed that the model was correlated with various immune-regulation-related pathways. Furthermore, pan-cancer cohorts and immunohistochemical analysis showed that the infiltration of tumor infiltrating lymphocytes (TILs) was lower in the high-score group. Additionally, the model could also predict the prognosis of patients with cervical cancer based on the expression of immune checkpoints (ICPs) in both the discovery and validation cohorts. Our study established and validated a metabolism-related prognostic model, which might improve the accuracy of predicting the clinical outcome of patients with cervical cancer and provide guidance for personalized treatment.
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29
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Carrasco K, Montersino C, Derviaux C, Saez-Ayala M, Hoffer L, Restouin A, Castellano R, Casassa J, Roche P, Pasquier E, Combes S, Morelli X, Collette Y, Betzi S. CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation. J Med Chem 2022; 65:5660-5674. [PMID: 35348328 DOI: 10.1021/acs.jmedchem.1c02168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Differentially screening the Fr-PPIChem chemical library on the bromodomain and extra-terminal (BET) BRD4-BDII versus -BDI bromodomains led to the discovery of a BDII-selective tetrahydropyridothienopyrimidinone (THPTP)-based compound. Structure-activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a potent inhibitor of BET proteins with a preferential and 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI). Its very low activity was demonstrated in various cell-based assays, corresponding with recent data describing other selective BDII compounds. However, screening on a drug sensitivity and resistance-profiling platform revealed its ability to modulate the anti-leukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. Altogether, the results confirm the originality of the THPTP molecular mode of action in the bromodomain (BD) cavity and its potential as a starting scaffold for the development of potent and selective bromodomain inhibitors.
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Affiliation(s)
- Kendall Carrasco
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France
| | - Camille Montersino
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France.,Institut Paoli-Calmettes, Plateforms HiTS & TrGET, Marseille 13009, France
| | - Carine Derviaux
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France.,Institut Paoli-Calmettes, Plateforms HiTS & TrGET, Marseille 13009, France
| | - Magali Saez-Ayala
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France
| | - Laurent Hoffer
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France
| | - Audrey Restouin
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France.,Institut Paoli-Calmettes, Plateforms HiTS & TrGET, Marseille 13009, France
| | - Rémy Castellano
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France.,Institut Paoli-Calmettes, Plateforms HiTS & TrGET, Marseille 13009, France
| | - Justine Casassa
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France
| | - Philippe Roche
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France
| | - Eddy Pasquier
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France
| | - Sébastien Combes
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France
| | - Xavier Morelli
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France.,Institut Paoli-Calmettes, Plateforms HiTS & TrGET, Marseille 13009, France
| | - Yves Collette
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France.,Institut Paoli-Calmettes, Plateforms HiTS & TrGET, Marseille 13009, France
| | - Stéphane Betzi
- CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France
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30
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Li B, Chen C, Jia J, He L. Research progress on antineoplastic, antibacterial, and anti-inflammatory activities of seven-membered heterocyclic derivatives. Curr Med Chem 2022; 29:5076-5096. [PMID: 35345989 DOI: 10.2174/0929867329666220328123953] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/20/2021] [Accepted: 12/30/2021] [Indexed: 11/22/2022]
Abstract
Abstract:
Seven-membered heterocyclic compounds are important drug scaffolds, because of their unique chemical structures. They widely exist in natural products and show a variety of biological activities. They have commonly been used in central nervous system drugs in the past 30 years. In the past decade, there are many studies on the activities of antitumor, antibacterial, etc. Herein, we summarize the research advances in different kinds of seven-membered heterocyclic compounds containing nitrogen, oxygen, and sulfur heteroatoms with antitumor, antisepsis, and anti-inflammation activities in the past ten years, which is expected to be beneficial to the development and design of novel drugs for the corresponding indications.
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Affiliation(s)
- Bin Li
- Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Chen Chen
- Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Jingjing Jia
- Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Ling He
- Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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31
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Li J, Zhang C, Xu H, Wang C, Dong R, Shen H, Zhuang X, Chen X, Li Q, Lu J, Zhang M, Wu X, Loomes KM, Zhou Y, Zhang Y, Liu J, Xu Y. Structure-Based Discovery and Optimization of Furo[3,2- c]pyridin-4(5 H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors. J Med Chem 2022; 65:5760-5799. [PMID: 35333526 DOI: 10.1021/acs.jmedchem.2c00100] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).
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Affiliation(s)
- Junhua Li
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China
| | - Cheng Zhang
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China
| | - Hongrui Xu
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Guangzhou Medical University, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Chao Wang
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China
| | - Ruibo Dong
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China
| | - Hui Shen
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China
| | - Xiaoxi Zhuang
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China
| | - Xiaoshan Chen
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China
| | - Qiu Li
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China
| | - Jibu Lu
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China
| | - Maofeng Zhang
- College of Pharmacy, Taizhou Polytechnic College, Taizhou 225300, China
| | - Xishan Wu
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China
| | - Kerry M Loomes
- School of Biological Sciences & Maurice Wilkins Centre, University of Auckland, Auckland 1010, New Zealand
| | - Yulai Zhou
- School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China
| | - Yan Zhang
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China
| | - Jinsong Liu
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yong Xu
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Guangzhou Medical University, Chinese Academy of Sciences, Guangzhou 510530, China.,China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou 510530, China.,State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
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32
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Järvenpää J, Rahnasto-Rilla M, Lahtela-Kakkonen M, Küblbeck J. Profiling the regulatory interplay of BET bromodomains and Sirtuins in cancer cell lines. Biomed Pharmacother 2022; 147:112652. [DOI: 10.1016/j.biopha.2022.112652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/14/2022] [Accepted: 01/14/2022] [Indexed: 12/27/2022] Open
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33
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Zhou L, Wang H. A Combined Feature Screening Approach of Random Forest and Filter-based Methods for Ultra-high Dimensional Data. Curr Bioinform 2022. [DOI: 10.2174/1574893617666220221120618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Various feature (variable) screening approaches have been proposed in the past decade to mitigate the impact of ultra-high dimensionality in classification and regression problems, including filter based methods such as sure indepen¬dence screening, and wrapper based methods such random forest. However, the former type of methods rely heavily on strong modelling assumptions while the latter ones requires an adequate sample size to make the data speak for themselves. These require¬ments can seldom be met in biochemical studies in cases where we have only access to ultra-high dimensional data with a complex structure and a small number of observations.
Objective:
In this research, we want to investigate the possibility of combing both filter based screening methods and random forest based screening methods in the regression context.
Method:
We have combined four state-of-art filter approaches, namely, sure independence screening (SIS) , robust rank corre¬lation based screening (RRCS), high dimensional ordinary least squares projection (HOLP) and a model free sure independence screening procedure based on the distance correlation (DCSIS) from the statistical community with a random forest based Boruta screening method from the machine learning community for regression problems.
Result:
Among all combined methods, RF-DCSIS performs better than the other methods in terms of screening accuracy and prediction capability on the simulated scenarios and real benchmark datasets.
Conclusion:
By empirical study from both extensive simulation and real data, we have shown that both filter based screening and random forest based screening have their pros and cons while a combination of both may lead to a better feature screening result and prediction capability
Keywords:
feature screening, filter-based method, ultra-high dimensional data, variable selection, random forest,RF-DCSIS
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Affiliation(s)
- Lifeng Zhou
- School of Economics and Management, Changsha University, China
| | - Hong Wang
- School of Mathematics and Statistics, Central South University, China
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34
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Image-Based Annotation of Chemogenomic Libraries for Phenotypic Screening. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27041439. [PMID: 35209227 PMCID: PMC8878468 DOI: 10.3390/molecules27041439] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/15/2022] [Accepted: 02/16/2022] [Indexed: 12/26/2022]
Abstract
Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation of identified hits often poses a challenge. The development of small molecules with narrow or exclusive target selectivity such as chemical probes and chemogenomic (CG) libraries, greatly diminishes this challenge, but non-specific effects caused by compound toxicity or interference with basic cellular functions still pose a problem to associate phenotypic readouts with molecular targets. Hence, each compound should ideally be comprehensively characterized regarding its effects on general cell functions. Here, we report an optimized live-cell multiplexed assay that classifies cells based on nuclear morphology, presenting an excellent indicator for cellular responses such as early apoptosis and necrosis. This basic readout in combination with the detection of other general cell damaging activities of small molecules such as changes in cytoskeletal morphology, cell cycle and mitochondrial health provides a comprehensive time-dependent characterization of the effect of small molecules on cellular health in a single experiment. The developed high-content assay offers multi-dimensional comprehensive characterization that can be used to delineate generic effects regarding cell functions and cell viability, allowing an assessment of compound suitability for subsequent detailed phenotypic and mechanistic studies.
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35
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Mukherjee T, Bhatt B, Prakhar P, Lohia GK, Rajmani R, Balaji KN. Epigenetic reader BRD4 supports mycobacterial pathogenesis by co-modulating host lipophagy and angiogenesis. Autophagy 2022; 18:391-408. [PMID: 34074211 PMCID: PMC8942508 DOI: 10.1080/15548627.2021.1936355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 05/23/2021] [Accepted: 05/26/2021] [Indexed: 10/21/2022] Open
Abstract
Mycobacterium tuberculosis (Mtb)-driven lipid accumulation is intricately associated with the progression of tuberculosis (TB) disease. Although several studies elucidating the mechanisms for lipid droplet (LD) biosynthesis exist, we provide evidence for the significance of their regulated turnover via macroautophagy/autophagy during Mtb infection. We demonstrate that Mtb utilizes EGFR (epidermal growth factor receptor) signaling to induce the expression of the histone acetylation reader, BRD4 (bromodomain containing 4). The EGFR-BRD4 axis suppresses lipid-specific autophagy, and hence favors cellular lipid accumulation. Specifically, we found that pharmacological inhibition or knockdown of Egfr or Brd4 enhances autophagic flux and concomitantly decreases cellular LDs that is otherwise maintained at a significant level in chloroquine-treated or Atg5 knocked down autophagy-compromised host cells. In line with the enhanced lipophagy, we found that loss of EGFR or BRD4 function restricts mycobacterial burden that is rescued by external replenishment with oleic acid. We also report that the EGFR-BRD4 axis exerts additional effects by modulating pro-angiogenic gene expression and consequently aberrant angiogenesis during mycobacterial infection. This is important in the context of systemic Mtb dissemination as well as for the efficient delivery of anti-mycobacterial therapeutics to the Mtb-rich core of TB granuloma. Finally, utilizing an in vivo mouse model of TB, we show that pharmacological inhibition of EGFR and BRD4 compromises LD buildup via enhanced lipophagy and normalizes angiogenesis, thereby restricting Mtb burden and rescuing mice from severe TB-like pathology. These findings shed light on the novel roles of BRD4 during Mtb infection, and its possible implication in potentiating anti-TB responses.Abbreviations: ATG5: autophagy related 5; BRDs: bromodomain containing; COL18A1: collagen type XVIII alpha 1 chain; EGFR: epidermal growth factor receptor; EP300: E1A binding protein p300; KDR: kinase insert domain receptor; KLF5: Kruppel like factor 5; LDs: lipid droplets; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; Mtb: Mycobacterium tuberculosis; PECAM1: platelet and endothelial cell adhesion molecule 1; SQSTM1/p62: sequestosome 1; TB: tuberculosis; THBS1: thrombospondin 1; VEGF: vascular endothelial growth factor.
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Affiliation(s)
- Tanushree Mukherjee
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Bharat Bhatt
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Praveen Prakhar
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Gaurav Kumar Lohia
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - R.S. Rajmani
- Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, India
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36
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Brown LJ, Achinger-Kawecka J, Portman N, Clark S, Stirzaker C, Lim E. Epigenetic Therapies and Biomarkers in Breast Cancer. Cancers (Basel) 2022; 14:474. [PMID: 35158742 PMCID: PMC8833457 DOI: 10.3390/cancers14030474] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/07/2022] [Accepted: 01/14/2022] [Indexed: 02/04/2023] Open
Abstract
Epigenetic therapies remain a promising, but still not widely used, approach in the management of patients with cancer. To date, the efficacy and use of epigenetic therapies has been demonstrated primarily in the management of haematological malignancies, with limited supportive data in solid malignancies. The most studied epigenetic therapies in breast cancer are those that target DNA methylation and histone modification; however, none have been approved for routine clinical use. The majority of pre-clinical and clinical studies have focused on triple negative breast cancer (TNBC) and hormone-receptor positive breast cancer. Even though the use of epigenetic therapies alone in the treatment of breast cancer has not shown significant clinical benefit, these therapies show most promise in use in combinations with other treatments. With improving technologies available to study the epigenetic landscape in cancer, novel epigenetic alterations are increasingly being identified as potential biomarkers of response to conventional and epigenetic therapies. In this review, we describe epigenetic targets and potential epigenetic biomarkers in breast cancer, with a focus on clinical trials of epigenetic therapies. We describe alterations to the epigenetic landscape in breast cancer and in treatment resistance, highlighting mechanisms and potential targets for epigenetic therapies. We provide an updated review on epigenetic therapies in the pre-clinical and clinical setting in breast cancer, with a focus on potential real-world applications. Finally, we report on the potential value of epigenetic biomarkers in diagnosis, prognosis and prediction of response to therapy, to guide and inform the clinical management of breast cancer patients.
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Affiliation(s)
- Lauren Julia Brown
- School of Clinical Medicine, St. Vincent’s Campus, University of New South Wales (UNSW), Sydney, NSW 2010, Australia; (L.J.B.); (J.A.-K.); (N.P.); (S.C.); (C.S.)
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Joanna Achinger-Kawecka
- School of Clinical Medicine, St. Vincent’s Campus, University of New South Wales (UNSW), Sydney, NSW 2010, Australia; (L.J.B.); (J.A.-K.); (N.P.); (S.C.); (C.S.)
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Neil Portman
- School of Clinical Medicine, St. Vincent’s Campus, University of New South Wales (UNSW), Sydney, NSW 2010, Australia; (L.J.B.); (J.A.-K.); (N.P.); (S.C.); (C.S.)
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Susan Clark
- School of Clinical Medicine, St. Vincent’s Campus, University of New South Wales (UNSW), Sydney, NSW 2010, Australia; (L.J.B.); (J.A.-K.); (N.P.); (S.C.); (C.S.)
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Clare Stirzaker
- School of Clinical Medicine, St. Vincent’s Campus, University of New South Wales (UNSW), Sydney, NSW 2010, Australia; (L.J.B.); (J.A.-K.); (N.P.); (S.C.); (C.S.)
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Elgene Lim
- School of Clinical Medicine, St. Vincent’s Campus, University of New South Wales (UNSW), Sydney, NSW 2010, Australia; (L.J.B.); (J.A.-K.); (N.P.); (S.C.); (C.S.)
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
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37
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Zhang J, Tang P, Zou L, Zhang J, Chen J, Yang C, He G, Liu B, Liu J, Chiang CM, Wang G, Ye T, Ouyang L. Discovery of Novel Dual-Target Inhibitor of Bromodomain-Containing Protein 4/Casein Kinase 2 Inducing Apoptosis and Autophagy-Associated Cell Death for Triple-Negative Breast Cancer Therapy. J Med Chem 2021; 64:18025-18053. [PMID: 34908415 PMCID: PMC10118286 DOI: 10.1021/acs.jmedchem.1c01382] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Bromodomain-containing protein 4 (BRD4) is an attractive epigenetic target in human cancers. Inhibiting the phosphorylation of BRD4 by casein kinase 2 (CK2) is a potential strategy to overcome drug resistance in cancer therapy. The present study describes the synthesis of multiple BRD4-CK2 dual inhibitors based on rational drug design, structure-activity relationship, and in vitro and in vivo evaluations, and 44e was identified to possess potent and balanced activities against BRD4 (IC50 = 180 nM) and CK2 (IC50 = 230 nM). In vitro experiments show that 44e could inhibit the proliferation and induce apoptosis and autophagy-associated cell death of MDA-MB-231 and MDA-MB-468 cells. In two in vivo xenograft mouse models, 44e displays potent anticancer activity without obvious toxicities. Taken together, we successfully synthesized the first highly effective BRD4-CK2 dual inhibitor, which is expected to be an attractive therapeutic strategy for triple-negative breast cancer (TNBC).
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Affiliation(s)
- Jifa Zhang
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Pan Tang
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Ling Zou
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Jin Zhang
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China.,School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Juncheng Chen
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Chengcan Yang
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Gu He
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Cheng-Ming Chiang
- Simmons Comprehensive Cancer Center, Department of Pharmacology, and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Guan Wang
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Tinghong Ye
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China
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38
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Hu G, Ma J, Zhang J, Chen Y, Liu H, Huang Y, Zheng J, Xu Y, Xue W, Zhai W. Hypoxia-induced lncHILAR promotes renal cancer metastasis via ceRNA for the miR-613/206/ 1-1-3p/Jagged-1/Notch/CXCR4 signaling pathway. Mol Ther 2021; 29:2979-2994. [PMID: 34058384 PMCID: PMC8531137 DOI: 10.1016/j.ymthe.2021.05.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 03/05/2021] [Accepted: 05/19/2021] [Indexed: 12/24/2022] Open
Abstract
Hypoxia has been identified as a common contributor to tumor progression, including invasion and metastasis. However, the underlying mechanisms of enhanced invasion and metastasis under hypoxia remain unclear. A hypoxic microenvironment promotes invasion and metastasis of renal cell carcinoma (RCC) by upregulating expression of LOC100506178, which we named hypoxia-induced long non-coding RNA (lncRNA) associated with RCC (lncHILAR). Knockdown of lncHILAR inhibited cell invasion and migration, whereas overexpression of lncHILAR, conversely, facilitated cell invasion and migration of RCC cells. Notably, hypoxic RCC cells secreted exosomes packaged with lncHILAR, which were taken up by normoxic RCC cells and then drove normoxic cell invasion. Mechanistically, lncHILAR elevated RCC invasion and metastasis by acting as a competing endogenous RNA (ceRNA) for miR-613/206/1-1-3p, which led to the upregulation of Jagged-1 and the C-X-C motif chemokine receptor 4 (CXCR4). Activation of the Jagged-1/Notch/CXCR4 axis induced RCC metastasis. lncHILAR promotes RCC cell invasion and metastasis via ceRNA for the miR-613/206/1-1-3p/Jagged-1/Notch/CXCR4 axis. The novel lncHILAR may thus serve as a potential biomarker and therapeutic target in RCC.
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Affiliation(s)
- Guanghui Hu
- State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Junjie Ma
- Department of Urology, Shanghai General Hospital, School of Medicine in Shanghai Jiao Tong University, Shanghai 200080, China
| | - Jin Zhang
- State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yonghui Chen
- State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Huan Liu
- Department of Urology, Shanghai Tenth People's Hospital, School of Medicine in Tongji University, Shanghai 200072, China
| | - Yiran Huang
- State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Junhua Zheng
- Department of Urology, Shanghai General Hospital, School of Medicine in Shanghai Jiao Tong University, Shanghai 200080, China
| | - Yunfei Xu
- Department of Urology, Shanghai Tenth People's Hospital, School of Medicine in Tongji University, Shanghai 200072, China.
| | - Wei Xue
- State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Wei Zhai
- State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
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39
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Fukano M, Park M, Deblois G. Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression. Cancers (Basel) 2021; 13:4699. [PMID: 34572926 PMCID: PMC8467722 DOI: 10.3390/cancers13184699] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 12/13/2022] Open
Abstract
Breast cancer progression is characterized by changes in cellular metabolism that contribute to enhanced tumour growth and adaptation to microenvironmental stresses. Metabolic changes within breast tumours are still poorly understood and are not as yet exploited for therapeutic intervention, in part due to a high level of metabolic heterogeneity within tumours. The metabolic profiles of breast cancer cells are flexible, providing dynamic switches in metabolic states to accommodate nutrient and energy demands and further aggravating the challenges of targeting metabolic dependencies in cancer. In this review, we discuss the intrinsic and extrinsic factors that contribute to metabolic heterogeneity of breast tumours. Next, we examine how metabolic flexibility, which contributes to the metabolic heterogeneity of breast tumours, can alter epigenetic landscapes and increase a variety of pro-tumorigenic functions. Finally, we highlight the difficulties in pharmacologically targeting the metabolic adaptations of breast tumours and provide an overview of possible strategies to sensitize heterogeneous breast tumours to the targeting of metabolic vulnerabilities.
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Affiliation(s)
- Marina Fukano
- Institute for Research in Immunology and Cancer (IRIC), University of Montréal, Montréal, QC H3T 1J4, Canada;
- Faculty of Medicine and Health Sciences, McGill University, Montréal, QC H3G 2M1, Canada;
- Rosalind & Morris Goodman Cancer Institute (GCI), McGill University, Montréal, QC H3A 1A3, Canada
| | - Morag Park
- Faculty of Medicine and Health Sciences, McGill University, Montréal, QC H3G 2M1, Canada;
- Rosalind & Morris Goodman Cancer Institute (GCI), McGill University, Montréal, QC H3A 1A3, Canada
| | - Geneviève Deblois
- Institute for Research in Immunology and Cancer (IRIC), University of Montréal, Montréal, QC H3T 1J4, Canada;
- Rosalind & Morris Goodman Cancer Institute (GCI), McGill University, Montréal, QC H3A 1A3, Canada
- Faculté de Pharmacie, Université de Montréal, Montréal, QC H3T 1J4, Canada
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40
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Mokhtari RB, Qorri B, Baluch N, Sparaneo A, Fabrizio FP, Muscarella LA, Tyker A, Kumar S, Cheng HLM, Szewczuk MR, Das B, Yeger H. Next-generation multimodality of nutrigenomic cancer therapy: sulforaphane in combination with acetazolamide actively target bronchial carcinoid cancer in disabling the PI3K/Akt/mTOR survival pathway and inducing apoptosis. Oncotarget 2021; 12:1470-1489. [PMID: 34316328 PMCID: PMC8310668 DOI: 10.18632/oncotarget.28011] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 06/14/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE Aberrations in the PI3K/AKT/mTOR survival pathway in many cancers are the most common genomic abnormalities. The phytochemical and bioactive agent sulforaphane (SFN) has nutrigenomic potential in activating the expression of several cellular protective genes via the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is primarily related to mechanisms of endogenous cellular defense and survival. The efficacy of SFN in combination with acetazolamide (AZ) was investigated in reducing typical H727 and atypical H720 BC survival, migration potential, and apoptosis in vitro and in vivo preclinical xenograft tissues. MATERIALS AND METHODS Microscopic imaging, immunocytochemistry, wound healing assay, caspase-cleaved cytokeratin 18 (M30, CCK18) CytoDeath ELISA assay, immunofluorescence labeling assays for apoptosis, hypoxia, Western Blotting, Tunnel assay, measurement of 5-HT secretion by carbon fiber amperometry assay, quantitative methylation-specific PCR (qMSP), morphologic changes, cell viability, apoptosis activity and the expression levels of phospho-Akt1, Akt1, HIF-1α, PI3K, p21, CAIX, 5-HT, phospho-mTOR, and mTOR in xenografts derived from typical H727 and atypical H720 BC cell lines. RESULTS Combining AZ+SFN reduced tumor cell survival compared to each agent alone, both in vitro and in vivo xenograft tissues. AZ+SFN targeted multiple pathways involved in cell cycle, serotonin secretion, survival, and growth pathways, highlighting its therapeutic approach. Both H727 and H720 cells were associated with induction of apoptosis, upregulation of the p21 cell cycle inhibitor, and downregulation of the PI3K/Akt/mTOR pathway, suggesting that the PI3K/Akt/mTOR pathway is a primary target of the AZ+SFN combination therapy. CONCLUSIONS Combining SFN+AZ significantly inhibits the PI3K/Akt/mTOR pathway and significantly reducing 5-HT secretion in carcinoid syndrome.
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Affiliation(s)
- Reza Bayat Mokhtari
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Experimental Therapeutics, Thoreau Laboratory for Global Health, M2D2, University of Massachusetts, Lowell, MA, USA.,Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Bessi Qorri
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Narges Baluch
- Department of Immunology and Allergy, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Angelo Sparaneo
- Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo FG, Italy
| | - Federico Pio Fabrizio
- Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo FG, Italy
| | - Lucia Anna Muscarella
- Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo FG, Italy
| | - Albina Tyker
- Department of Internal Medicine, University of Chicago, Chicago, IL, USA
| | - Sushil Kumar
- Q.P.S. Holdings LLC, Pencader Corporate Center, Newark, DE, USA
| | - Hai-Ling Margaret Cheng
- Institute of Biomedical Engineering, The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, Canada
| | - Myron R Szewczuk
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Bikul Das
- Department of Experimental Therapeutics, Thoreau Laboratory for Global Health, M2D2, University of Massachusetts, Lowell, MA, USA.,Department of Cancer and Stem Cell Biology, KaviKrishna Laboratory, Guwahati Biotech Park, Indian Institute of Technology, Guwahati, Assam, India.,Department of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA, USA
| | - Herman Yeger
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
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41
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He MY, Halford MM, Liu R, Roy JP, Grant ZL, Coultas L, Thio N, Gilan O, Chan YC, Dawson MA, Achen MG, Stacker SA. Three-dimensional CRISPR screening reveals epigenetic interaction with anti-angiogenic therapy. Commun Biol 2021; 4:878. [PMID: 34267311 PMCID: PMC8282794 DOI: 10.1038/s42003-021-02397-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/23/2021] [Indexed: 12/13/2022] Open
Abstract
Angiogenesis underlies development, physiology and pathogenesis of cancer, eye and cardiovascular diseases. Inhibiting aberrant angiogenesis using anti-angiogenic therapy (AAT) has been successful in the clinical treatment of cancer and eye diseases. However, resistance to AAT inevitably occurs and its molecular basis remains poorly understood. Here, we uncover molecular modifiers of the blood endothelial cell (EC) response to a widely used AAT bevacizumab by performing a pooled genetic screen using three-dimensional microcarrier-based cell culture and CRISPR–Cas9. Functional inhibition of the epigenetic reader BET family of proteins BRD2/3/4 shows unexpected mitigating effects on EC survival and/or proliferation upon VEGFA blockade. Moreover, transcriptomic and pathway analyses reveal an interaction between epigenetic regulation and anti-angiogenesis, which may affect chromosomal structure and activity in ECs via the cell cycle regulator CDC25B phosphatase. Collectively, our findings provide insight into epigenetic regulation of the EC response to VEGFA blockade and may facilitate development of quality biomarkers and strategies for overcoming resistance to AAT. Through three-dimensional CRISPR screening, He et al. report that functional inhibition of BET family of proteins BRD2/3/4 shows mitigating effects on blood endothelial cell (EC) survival and/or proliferation upon VEGFA blockade. An interaction between epigenetic regulation and anti-angiogenesis, which may affect chromosomal structure and activity in ECs through CDC25B phosphatase, is potentially involved with EC resistance to anti-angiogenic therapy.
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Affiliation(s)
- Michael Y He
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.,Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Michael M Halford
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Ruofei Liu
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
| | - James P Roy
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
| | - Zoe L Grant
- Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.,Gladstone Institutes, San Francisco, CA, USA
| | - Leigh Coultas
- Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Niko Thio
- Bioinformatics Core, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Omer Gilan
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.,Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
| | - Yih-Chih Chan
- Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Mark A Dawson
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.,Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Centre for Cancer Research, The University of Melbourne, Parkville, VIC, Australia.,Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Marc G Achen
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.,Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.,St Vincent's Institute of Medical Research, Melbourne, VIC, Australia
| | - Steven A Stacker
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. .,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. .,Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
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42
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Lucas SCC, Atkinson SJ, Chung CW, Davis R, Gordon L, Grandi P, Gray JJR, Grimes T, Phillipou A, Preston AG, Prinjha RK, Rioja I, Taylor S, Tomkinson NCO, Wall I, Watson RJ, Woolven J, Demont EH. Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors. J Med Chem 2021; 64:10711-10741. [PMID: 34260229 DOI: 10.1021/acs.jmedchem.1c00344] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.
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Affiliation(s)
| | | | | | | | | | - Paola Grandi
- IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany
| | | | | | | | | | | | | | | | - Nicholas C O Tomkinson
- WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 259 Cathedral Street, Glasgow G1 1XL, U.K
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43
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Brand M, Clayton J, Moroglu M, Schiedel M, Picaud S, Bluck JP, Skwarska A, Bolland H, Chan AKN, Laurin CMC, Scorah AR, See L, Rooney TPC, Andrews KH, Fedorov O, Perell G, Kalra P, Vinh KB, Cortopassi WA, Heitel P, Christensen KE, Cooper RI, Paton RS, Pomerantz WCK, Biggin PC, Hammond EM, Filippakopoulos P, Conway SJ. Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain. J Med Chem 2021; 64:10102-10123. [PMID: 34255515 PMCID: PMC8311651 DOI: 10.1021/acs.jmedchem.1c00348] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
![]()
CREBBP (CBP/KAT3A)
and its paralogue EP300 (KAT3B) are lysine acetyltransferases
(KATs) that are essential for human development. They each comprise
10 domains through which they interact with >400 proteins, making
them important transcriptional co-activators and key nodes in the
human protein–protein interactome. The bromodomains of CREBBP
and EP300 enable the binding of acetylated lysine residues from histones
and a number of other important proteins, including p53, p73, E2F,
and GATA1. Here, we report a work to develop a high-affinity, small-molecule
ligand for the CREBBP and EP300 bromodomains [(−)-OXFBD05]
that shows >100-fold selectivity over a representative member of
the
BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate
that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon
cancer cells results in lowered levels of c-Myc and a reduction in
H3K18 and H3K27 acetylation. In hypoxia (<0.1% O2),
the inhibition of the CREBBP/EP300 bromodomain results in the enhanced
stabilization of HIF-1α.
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Affiliation(s)
- Michael Brand
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - James Clayton
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Mustafa Moroglu
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Matthias Schiedel
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Sarah Picaud
- Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 3TA, U.K
| | - Joseph P Bluck
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.,Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K
| | - Anna Skwarska
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, U.K
| | - Hannah Bolland
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, U.K
| | - Anthony K N Chan
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Corentine M C Laurin
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Amy R Scorah
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Larissa See
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Timothy P C Rooney
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Katrina H Andrews
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Oleg Fedorov
- Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 3TA, U.K
| | - Gabriella Perell
- Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
| | - Prakriti Kalra
- Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
| | - Kayla B Vinh
- Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
| | - Wilian A Cortopassi
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Pascal Heitel
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Kirsten E Christensen
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Richard I Cooper
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Robert S Paton
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.,Department of Chemistry, Colorado State University, 1301 Center Ave, Ft. Collins, Colorado 80523-1872, United States
| | - William C K Pomerantz
- Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
| | - Philip C Biggin
- Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K
| | - Ester M Hammond
- Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, U.K
| | - Panagis Filippakopoulos
- Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 3TA, U.K
| | - Stuart J Conway
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
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44
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Rianjongdee F, Atkinson SJ, Chung CW, Grandi P, Gray JRJ, Kaushansky LJ, Medeiros P, Messenger C, Phillipou A, Preston A, Prinjha RK, Rioja I, Satz AL, Taylor S, Wall ID, Watson RJ, Yao G, Demont EH. Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit. J Med Chem 2021; 64:10806-10833. [PMID: 34251219 DOI: 10.1021/acs.jmedchem.1c00412] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.
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Affiliation(s)
| | | | | | - Paola Grandi
- IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstr. 1, Heidelberg 69117, Germany
| | | | - Laura J Kaushansky
- Encoded Library Technologies, R&D Medicinal Science and Technology, GSK, 200 Cambridge Park Drive, Cambridge 02140, Massachusetts, United States
| | - Patricia Medeiros
- Encoded Library Technologies, R&D Medicinal Science and Technology, GSK, 200 Cambridge Park Drive, Cambridge 02140, Massachusetts, United States
| | | | | | | | | | | | | | | | | | | | - Gang Yao
- Encoded Library Technologies, R&D Medicinal Science and Technology, GSK, 200 Cambridge Park Drive, Cambridge 02140, Massachusetts, United States
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45
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Harrison LA, Atkinson SJ, Bassil A, Chung CW, Grandi P, Gray JRJ, Levernier E, Lewis A, Lugo D, Messenger C, Michon AM, Mitchell DJ, Preston A, Prinjha RK, Rioja I, Seal JT, Taylor S, Wall ID, Watson RJ, Woolven JM, Demont EH. Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins. J Med Chem 2021; 64:10742-10771. [PMID: 34232650 DOI: 10.1021/acs.jmedchem.0c02155] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.
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Affiliation(s)
- Lee A Harrison
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Stephen J Atkinson
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Anna Bassil
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Chun-Wa Chung
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Paola Grandi
- IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstr. 1, 69117 Heidelberg, Germany
| | - James R J Gray
- Quantitative Pharmacology, Immunoinflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Etienne Levernier
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Antonia Lewis
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - David Lugo
- Quantitative Pharmacology, Immunoinflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Cassie Messenger
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Anne-Marie Michon
- IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstr. 1, 69117 Heidelberg, Germany
| | - Darren J Mitchell
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Alex Preston
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Rab K Prinjha
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Inmaculada Rioja
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Jonathan T Seal
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Simon Taylor
- Quantitative Pharmacology, Immunoinflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Ian D Wall
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Robert J Watson
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - James M Woolven
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Emmanuel H Demont
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
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46
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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47
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Qin F, Zhou H, Li J, Liu J, Wang Y, Bai R, Liu S, Ma M, Liu T, Gao F, Du P, Lu X, Chen C. Hypoxia and pH co-triggered oxidative stress amplifier for tumor therapy. Eur J Pharmacol 2021; 905:174187. [PMID: 34048738 DOI: 10.1016/j.ejphar.2021.174187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 05/01/2021] [Accepted: 05/12/2021] [Indexed: 11/19/2022]
Abstract
To keep fast proliferation, tumor cells are exposed to higher oxidative stress than normal cells and they upregulate the amount of some antioxidants such as glutathione (GSH) against reactive oxygen species to maintain the balance. This phenomenon is severe in hypoxic tumor cells. Although researchers have proposed a series of treatment strategies based on regulating the intracellular reactive oxygen species level, few of them are related to the hypoxic tumor. Herein, a novel organic compound (PLC) was designed by using lysine as a bridge to connect two functional small molecules, a hypoxia-responsive nitroimidazole derivative (pimonidazole) and a pH-responsive cinnamaldehyde (CA) derivative. Then, the oxidative stress amplifying ability of PLC in hypoxic tumor cells was evaluated. The acidic microenvironment of tumor can trigger the release of CA to produce reactive oxygen species. Meanwhile, large amount of nicotinamide adenine dinucleotide phosphate (NADPH) can be consumed to decrease the synthesis of GSH during the bio-reduction process of the nitro group in PLC under hypoxic conditions. Therefore, the lethal effect of CA can be amplified for the decrease of GSH. Our results prove that this strategy can significantly enhance the therapeutic effect of CA in the hypoxic tumor cells.
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Affiliation(s)
- Fenglan Qin
- Tianjin Key Laboratory of Molecular Optoelectronic, Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, PR China; CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China
| | - Huige Zhou
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China; Research Unit of Nanoscience and Technology, Chinese Academy of Medical Sciences, Beijing, 100021, PR China
| | - Jiayang Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China; Research Unit of Nanoscience and Technology, Chinese Academy of Medical Sciences, Beijing, 100021, PR China
| | - Jing Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China
| | - Yaling Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China; Research Unit of Nanoscience and Technology, Chinese Academy of Medical Sciences, Beijing, 100021, PR China
| | - Ru Bai
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China
| | - Shihui Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China
| | - Manman Ma
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China
| | - Tao Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China
| | - Fene Gao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China
| | - Peiyao Du
- Tianjin Key Laboratory of Molecular Optoelectronic, Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, PR China.
| | - Xiaoquan Lu
- Tianjin Key Laboratory of Molecular Optoelectronic, Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, PR China.
| | - Chunying Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China; Research Unit of Nanoscience and Technology, Chinese Academy of Medical Sciences, Beijing, 100021, PR China.
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48
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Shibasaki H, Kinoh H, Cabral H, Quader S, Mochida Y, Liu X, Toh K, Miyano K, Matsumoto Y, Yamasoba T, Kataoka K. Efficacy of pH-Sensitive Nanomedicines in Tumors with Different c-MYC Expression Depends on the Intratumoral Activation Profile. ACS NANO 2021; 15:5545-5559. [PMID: 33625824 DOI: 10.1021/acsnano.1c00364] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Effective inhibition of the protein derived from cellular myelocytomatosis oncogene (c-Myc) is one of the most sought-after goals in cancer therapy. While several c-Myc inhibitors have demonstrated therapeutic potential, inhibiting c-Myc has proven challenging, since c-Myc is essential for normal tissues and tumors may present heterogeneous c-Myc levels demanding contrasting therapeutic strategies. Herein, we developed tumor-targeted nanomedicines capable of treating both tumors with high and low c-Myc levels by adjusting their ability to spatiotemporally control drug action. These nanomedicines loaded homologues of the bromodomain and extraterminal (BET) motif inhibitor JQ1 as epigenetic c-Myc inhibitors through pH-cleavable bonds engineered for fast or slow drug release at intratumoral pH. In tumors with high c-Myc expression, the fast-releasing (FR) nanomedicines suppressed tumor growth more effectively than the slow-releasing (SR) ones, whereas, in the low c-Myc tumors, the efficacy of the nanomedicines was the opposite. By studying the tumor distribution and intratumoral activation of the nanomedicines, we found that, despite SR nanomedicines achieved higher accumulation than the FR counterparts in both c-Myc high and low tumors, the antitumor activity profiles corresponded with the availability of activated drugs inside the tumors. These results indicate the potential of engineered nanomedicines for c-Myc inhibition and spur the idea of precision pH-sensitive nanomedicine based on cancer biomarker levels.
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Affiliation(s)
- Hitoshi Shibasaki
- Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Hiroaki Kinoh
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Horacio Cabral
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Sabina Quader
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Yuki Mochida
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Xueying Liu
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Kazuko Toh
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Kazuki Miyano
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
- Department of Otorhinolaryngology, Tokyo Yamate Medical Center, 3-22-1, Hyakunin-cho, Shinjuku-ku, Tokyo 169-0073, Japan
| | - Yu Matsumoto
- Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Tatsuya Yamasoba
- Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Kazunori Kataoka
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
- Policy Alternative Research Institute, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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49
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Aylott HE, Atkinson SJ, Bamborough P, Bassil A, Chung CW, Gordon L, Grandi P, Gray JRJ, Harrison LA, Hayhow TG, Messenger C, Mitchell D, Phillipou A, Preston A, Prinjha RK, Rianjongdee F, Rioja I, Seal JT, Wall ID, Watson RJ, Woolven JM, Demont EH. Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors. J Med Chem 2021; 64:3249-3281. [PMID: 33662213 DOI: 10.1021/acs.jmedchem.0c02156] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).
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Affiliation(s)
- Helen E Aylott
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Stephen J Atkinson
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Paul Bamborough
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Anna Bassil
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Chun-Wa Chung
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Laurie Gordon
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Paola Grandi
- IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstr. 1, Heidelberg 69117, Germany
| | - James R J Gray
- Quantitative Pharmacology, Immunoinflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Lee A Harrison
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Thomas G Hayhow
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Cassie Messenger
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Darren Mitchell
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Alexander Phillipou
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Alex Preston
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Rab K Prinjha
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Francesco Rianjongdee
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Inmaculada Rioja
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Jonathan T Seal
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Ian D Wall
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Robert J Watson
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - James M Woolven
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Emmanuel H Demont
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K
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50
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Qiao H, Chen X, Wang Q, Zhang J, Huang D, Chen E, Qian H, Zhong Y, Tang Q, Chen W. Tumor localization of oncolytic adenovirus assisted by pH-degradable microgels with JQ1-mediated boosting replication and PD-L1 suppression for enhanced cancer therapy. Biomater Sci 2021; 8:2472-2480. [PMID: 32196028 DOI: 10.1039/d0bm00172d] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Oncolytic therapy is a fast-developing cancer treatment field based on the promising clinical performance from the selective tumor cell killing and induction of systemic antitumor immunity. The virotherapy efficacy, however, is strongly hindered by the limited virus propagation and negative immune regulation in the tumor microenvironments. To enhance the antitumor activity, we developed injectable pH-degradable PVA microgels encapsulated with oncolytic adenovirus (OA) by microfluidics for localized OA delivery and cancer treatments. PVA microgels were tailored with an OA encapsulation efficiency of 68% and exhibited a pH-dependent OA release as the microgel degradation at mildly acidic conditions. PVA microgels mediated fast viral release and increased replication in HEK293T and A549 cells at a lower pH, and the replication efficiency could be further reinforced by co-loading with one BET bromodomain inhibitor JQ1, inducing significant cytotoxicity against A549 cells. An in vivo study revealed that OA release was highly located at the tumor tissue assisted by PVA microgels, and the OA infection was also enhanced with the addition of JQ1 treatment, meanwhile greatly inhibiting the PD-L1 expression to overcome the immune suppression. OA/JQ1 co-encapsulated injectable microgels exhibited a superior in vivo antitumor activity on the A549 lung tumor-bearing mice by the combination of inhibited proliferation, amplified oncolysis, and potential immune regulation.
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Affiliation(s)
- Haishi Qiao
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Xingmei Chen
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Qiming Wang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, PR China
| | - Junmei Zhang
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Dechun Huang
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Enping Chen
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Hongliang Qian
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Yinan Zhong
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Qi Tang
- Key Laboratory of Antibody Technology, National Health Commission, Nanjing Medical University, Nanjing 211166, PR China.
| | - Wei Chen
- Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.
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