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JOURNAL ARTICLE
Yu-Hsuan Hung, Hui-Ching Wang, Mei-Ren Pan, Li-Tzong Chen
Gastrointestinal (GI) cancers are some of the main public health threats to the world. Even though surgery, chemotherapy, and targeted therapy are available for their treatments, these approaches provide limited success in reducing mortality, making the identification of additional therapeutic targets mandatory. Chromatin remodeling in cancer has long been studied and related therapeutics are widely used, although less is known about factors with prognostic and therapeutic potential in such areas as gastrointestinal cancers...
February 20, 2024: Journal of Personalized Medicine
#22
JOURNAL ARTICLE
Yuki Kotani, Yoshinori Imura, Sho Nakai, Ryota Chijimatsu, Haruna Takami, Akitomo Inoue, Hirokazu Mae, Satoshi Takenaka, Hidetatsu Outani, Seiji Okada
Synovial sarcoma (SS), a rare subtype of soft-tissue sarcoma distinguished by expression of the fusion gene SS18-SSX, predominantly affects the extremities of young patients. Existing anticancer drugs have limited efficacy against this malignancy, necessitating the development of innovative therapeutic approaches. Given the established role of SS18-SSX in epigenetic regulation, we focused on bromodomain and extra-terminal domain protein (BET) inhibitors and epigenetic agents. Our investigation of the BET inhibitor ABBV-075 revealed its pronounced antitumor effects, inducing G1-phase cell-cycle arrest and apoptosis, in four SS cell lines...
March 11, 2024: Cancers
#23
JOURNAL ARTICLE
Maria Laura Saiz, Laura Lozano-Chamizo, Aida Bernardo Florez, Marzia Marciello, Paula Diaz-Bulnes, Viviana Corte-Iglesias, Cristian Ruiz Bernet, Raul R Rodrigues-Diez, Cristina Martin-Martin, Mar Rodriguez-Santamaria, Ivan Fernandez-Vega, Ramon M Rodriguez, Carmen Diaz-Corte, Beatriz Suarez-Alvarez, Marco Filice, Carlos Lopez-Larrea
Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1 has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, its clinical translation faces challenges due to issues with poor pharmacokinetics and side effects. Here, we developed engineered liposomes loaded with JQ1 with the aim of enhancing kidney drug delivery and reducing the required minimum effective dose by leveraging cargo protection...
March 26, 2024: Biomedicine & Pharmacotherapy
#24
JOURNAL ARTICLE
Liya Bai, Hui Liu, Ran You, Xiaoyu Jiang, Tao Zhang, Yunan Li, Tianhe Shan, Zhanyin Qian, Yinsong Wang, Yuanyuan Liu, Chunyu Li
Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs)...
March 27, 2024: Molecular Pharmaceutics
#25
JOURNAL ARTICLE
Jasmine Manji, Jasmine Pipella, Gabriel Brawerman, Peter J Thompson
Type 1 diabetes (T1D) is a metabolic disease resulting from progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the majority of beta cells are lost in T1D, a small subset undergoes senescence, a stress response involving growth arrest, DNA damage response, and activation of a senescence-associated secretory phenotype (SASP). SASP in beta cells of the nonobese diabetic (NOD) mouse model of T1D and primary human islets is regulated at the level of transcription by bromodomain extra-terminal (BET) proteins, but the mechanisms remain unclear...
March 6, 2024: Epigenomes
#26
REVIEW
Magdalena Strachowska, Agnieszka Robaszkiewicz
Due to the contribution of highly homologous acetyltransferases CBP and p300 to transcription elevation of oncogenes and other cancer promoting factors, these enzymes emerge as possible epigenetic targets of anticancer therapy. Extensive efforts in search for small molecule inhibitors led to development of compounds targeting histone acetyltransferase catalytic domain or chromatin-interacting bromodomain of CBP/p300, as well as dual BET and CBP/p300 inhibitors. The promising anticancer efficacy in in vitro and mice models led CCS1477 and NEO2734 to clinical trials...
March 21, 2024: Pharmacology & Therapeutics
#27
JOURNAL ARTICLE
Francesca Reggiani, Giovanna Talarico, Giulia Gobbi, Elisabetta Sauta, Federica Torricelli, Veronica Manicardi, Eleonora Zanetti, Stefania Orecchioni, Paolo Falvo, Simonetta Piana, Filippo Lococo, Massimiliano Paci, Francesco Bertolini, Alessia Ciarrocchi, Valentina Sancisi
Non-small-cell lung carcinoma (NSCLC) is the most common lung cancer and one of the pioneer tumors in which immunotherapy has radically changed patients' outcomes. However, several issues are emerging and their implementation is required to optimize immunotherapy-based protocols. In this work, we investigate the ability of the Bromodomain and Extra-Terminal protein inhibitors (BETi) to stimulate a proficient anti-tumor immune response toward NSCLC. By using in vitro, ex-vivo, and in vivo models, we demonstrate that these epigenetic drugs specifically enhance Natural Killer (NK) cell cytotoxicity...
March 22, 2024: Nature Communications
#28
JOURNAL ARTICLE
Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.
Tomohiko Sato, Kenichi Yoshida, Tsutomu Toki, Rika Kanezaki, Kiminori Terui, Ryunosuke Saiki, Masami Ojima, Yotaro Ochi, Seiya Mizuno, Masaharu Yoshihara, Tamayo Uechi, Naoya Kenmochi, Shiro Tanaka, Jun Matsubayashi, Kenta Kisai, Ko Kudo, Kentaro Yuzawa, Yuka Takahashi, Tatsuhiko Tanaka, Yohei Yamamoto, Akie Kobayashi, Takuya Kamio, Shinya Sasaki, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Hideki Muramatsu, Asahito Hama, Daisuke Hasegawa, Atsushi Sato, Katsuyoshi Koh, Shuhei Karakawa, Masao Kobayashi, Junichi Hara, Yuichi Taneyama, Chihaya Imai, Daiichiro Hasegawa, Naoto Fujita, Masahiro Yoshitomi, Shotaro Iwamoto, Genki Yamato, Satoshi Saida, Nobutaka Kiyokawa, Takao Deguchi, Masafumi Ito, Hidemasa Matsuo, Souichi Adachi, Yasuhide Hayashi, Takashi Taga, Akiko Moriya Saito, Keizo Horibe, Kenichiro Watanabe, Daisuke Tomizawa, Satoru Miyano, Satoru Takahashi, Seishi Ogawa, Etsuro Ito
Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse, and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing...
March 21, 2024: Blood
#29
JOURNAL ARTICLE
Mengnuo Chen, Sara Mainardi, Cor Lieftink, Arno Velds, Iris de Rink, Chen Yang, Hendrik J Kuiken, Ben Morris, Finn Edwards, Fleur Jochems, Olaf van Tellingen, Manon Boeije, Natalie Proost, Robin A Jansen, Shifan Qin, Haojie Jin, J C Koen van der Mijn, Arnout Schepers, Subramanian Venkatesan, Wenxin Qin, Roderick L Beijersbergen, Liqin Wang, René Bernards
Drug-tolerant persisters (DTPs) are a rare subpopulation of cells within a tumor that can survive therapy through nongenetic adaptive mechanisms to develop relapse and repopulate the tumor following drug withdrawal. Using a cancer cell line with an engineered suicide switch to kill proliferating cells, we perform both genetic screens and compound screens to identify the inhibition of bromodomain and extraterminal domain (BET) proteins as a selective vulnerability of DTPs. BET inhibitors are especially detrimental to DTPs that have reentered the cell cycle (DTEPs) in a broad spectrum of cancer types...
March 19, 2024: Cell reports medicine
#30
JOURNAL ARTICLE
Ye Feng, Haider Mahdi, Richard Piekarz, Jan H Beumer, Timothy W Synold
We have developed and validated a novel LC-MS/MS method for the simultaneous quantification of ZEN-3694 and its active metabolite ZEN-3791 in human plasma after protein precipitation. Stable isotope-labeled versions were used as internal standards. Chromatographic separation was achieved on a Kinetex C18 column using 0.1% formic acid in H2 O and 0.1% formic acid in MeOH as mobile phases. Detection was performed via positive electrospray ionization mode with multiple reaction monitoring. The assay exhibited linearity in the concentration range of 5-5000 ng/ml for both analytes...
March 18, 2024: Bioanalysis
#31
JOURNAL ARTICLE
Alexander Bigger-Allen, Ali Hashemi Gheinani, Rosalyn M Adam
BACKGROUND: Injury to contractile organs such as the heart, vasculature, urinary bladder and gut can stimulate a pathological response that results in loss of normal contractility. PDGF and TGFβ are among the most well studied initiators of the injury response and have been shown to induce aberrant contraction in mechanically active cells of hollow organs including smooth muscle cells (SMC) and fibroblasts. However, the mechanisms driving contractile alterations downstream of PDGF and TGFβ in SMC and fibroblasts are incompletely understood, limiting therapeutic interventions...
March 16, 2024: Cell Communication and Signaling: CCS
#32
REVIEW
Hevna Dhulkifle, Mohammad Issam Diab, Majed Algonaiah, Hesham M Korashy, Zaid H Maayah
Bromodomain and extra-terminal domain proteins (BET proteins) are epigenetic reader proteins that have been implicated in regulating gene expression through binding to chromatin and interaction with transcription factors. These proteins are located in the nucleus and are responsible for recognizing acetylated lysine residues on histones, reading epigenetic messages, recruiting key transcription factors, and thereby regulating gene expression. BET proteins control the transcription of genes responsible for maladaptive effects in inflammation, cancer, and renal and cardiovascular diseases...
March 8, 2024: ACS Pharmacology & Translational Science
#33
JOURNAL ARTICLE
Yeorae Kim, Wook-Ha Park, Dong-Hoon Suh, Kidong Kim, Jae-Hong No, Yong-Beom Kim
Efforts have been made to develop bromodomain inhibitors as cancer treatments. Sub-pathways, particularly in ovarian cancer, affected by bromodomain-containing protein (BRD) remain unclear. This study verified the antitumor effects of a new drug that can overcome OPT-0139-chemoresistance to treat ovarian cancer. A mouse xenograft model of human ovarian cancer cells, SKOV3 and OVCAR3, was used in this study. Cell viability and proliferation were assessed using MTT and ATP assays. Cell cycle arrest and apoptosis were determined using flow cytometry...
February 27, 2024: Cancers
#34
JOURNAL ARTICLE
Monica Viviano, Alessandra Cipriano, Emanuele Fabbrizi, Alessandra Feoli, Sabrina Castellano, Gianluca Sbardella, Antonello Mai, Ciro Milite, Dante Rotili
INTRODUCTION: Bromodomain and ExtraTerminal (BET) domain proteins are transcriptional cofactors that, recognizing acetylated lysines of histone and non-histone proteins, can modulate gene expression. The BET family consists of four members, each of which contains two bromodomains (BD1 and BD2) able to recognize the acetylated mark. Pan-BET inhibitors (BETi) have shown a promising anticancer potential in many clinical trials; however, their further development has been in part hampered by the side effects due to their lack of selectivity...
March 11, 2024: Expert Opinion on Therapeutic Patents
#35
Tongchen He, Caleb Cheng, Yuanyuan Qiao, Hanbyul Cho, Eleanor Young, Rahul Mannan, Somnath Mahapatra, Stephanie J Miner, Yang Zheng, NamHoon Kim, Victoria Z Zeng, Jasmine P Wisniewski, Siyu Hou, Bailey Jackson, Xuhong Cao, Fengyun Su, Rui Wang, Yu Chang, Bilash Kuila, Subhendu Mukherjee, Sandeep Dukare, Kiran B Aithal, Samiulla D S, Chandrasekhar Abbineni, Costas A Lyssiotis, Abhijit Parolia, Lanbo Xiao, Arul M Chinnaiyan
UNLABELLED: Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients...
March 2, 2024: bioRxiv
#36
JOURNAL ARTICLE
Min Bai, Yunpeng Huang, Xinrui Suo, Lieyang Wang, Weie Han, Weihua Zhang
OBJECTIVE: Follicular lymphoma (FL) is an indolent B-cell lymphoproliferative disorder, characterized by a lymphoid follicular pattern of growth. PFI-1 or CPI-203 has been known to effectively promote the inhibition of primary effusion lymphoma progression. This study aimed at investigating the anti-tumor properties of PFI-1 and CPI-203 on FL cells and uncover the underlying mechanism of action. METHODS: FL cells were treated with PFI-1 and CPI-203, and the treated cells were evaluated for their cell viability, cell cycle and apoptosis using CCK8, flow cytometry, and Western blot assays...
March 15, 2024: Heliyon
#37
JOURNAL ARTICLE
You Chen, Tong Zhao, Mengyu Han, Yi Chen
OBJECTIVE: Cataract causes the greatest number of blindnesses worldwide. This study aims to investigate the role of miR-143 in lens epithelial cells. METHODS: Clustering analysis was conducted to systematically compare miRNA expression levels across cataract and myopia. The levels of miR-143 and Bromodomain containing 2 (BRD2) were determined using real-time quantitative PCR (RT-qPCR) assay in lens epithelial cells. Transwell and wound healing assays were conducted to detect cell invasive and migratory abilities...
2024: American Journal of Translational Research
#38
JOURNAL ARTICLE
Simon T Jakobsen, Rikke A M Jensen, Maria S Madsen, Tina Ravnsborg, Christian S Vaagenso, Majken S Siersbæk, Hjorleifur Einarsson, Robin Andersson, Ole N Jensen, Rasmus Siersbæk
The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC directly regulates enhancer activity to promote cancer type-specific gene programs predictive of poor patient prognosis...
March 7, 2024: Nature Genetics
#39
JOURNAL ARTICLE
Rong Liu, Xiaodie Chen, Jiali Li, Xingyun Liu, Mao Shu
Bromine-containing domain protein 4 (BRD4) plays a crucial role in regulating transcription and genome stability. Selective inhibitors of BRD4-BD1 can specifically target specific bromine domains to affect cell proliferation, apoptosis, and differentiation. In this work, 43 selective benzoazepinone BRD4-BD1 inhibitors were studied using molecular simulations and three-dimensional quantitative conformation relationships (3D-QSAR). A reliable 3D-QSAR model was established based on COMFA (Q2 = 0...
February 29, 2024: Journal of Biomolecular Structure & Dynamics
#40
JOURNAL ARTICLE
Clemens Lang, Sandra Stickler, Barbara Rath, Maryana Teufelsbauer, Lukas Weigl, Martin Hohenegger, Gerhard Hamilton
BACKGROUND/AIM: Osteosarcoma at an advanced stage has a poor outcome, and novel targeted therapies are needed, especially for metastatic disease. Bromodomain inhibitors (BETi) are epigenetic modulators that broadly impair the expression of oncogenic proteins and exert antitumor effects. BETi can be combined with chemotherapeutics to increase therapeutic responses with superior effects in the form of proteolysis targeting chimeras (PROTACs) that degrade proteins of interest (POI) in multiple cycles...
March 2024: Anticancer Research
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