Although having promising anti-myeloma properties, the pan-histone deacetylase inhibitor (HDACi) panobinostat lacks therapeutic activity as a single agent. The aim of the current study was to elucidate the mechanisms underlying multiple myeloma (MM) resistance to panobinostat monotherapy and to define strategies to overcome it. Sensitivity of MM cell lines and primary CD138+ cells from MM patients to panobinostat correlated with reduced expression of the chemokine receptor CXCR4, whereas overexpression of CXCR4 in MM cell lines increased their resistance to panobinostat. Decreased sensitivity to HDACi was associated with reversible G0/G1 cell growth arrest while response was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators revealed the pro-survival mTOR pathway to be regulated by CXCR4 overexpression. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance to HDACi and induced synergistic cell death. The combination of panobinostat/everolimus resulted in sustained DNA damage and irreversible suppression of proliferation accompanied by robust apoptosis. Gene expression analysis revealed distinct genetic profiles of single versus combined agent exposure. Whereas panobinostat increased the expression of the cell cycle inhibitor p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated the expression of DNA repair genes and mitotic checkpoint regulators. Importantly, the combination of panobinostat with everolimus effectively targeted CXCR4-expressing resistant MM cells in vivo in the BM niche. In summary, our results uncover the mechanism responsible for the strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel potential therapeutic approach to treat MM.
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http://dx.doi.org/10.1016/j.bcp.2019.07.016 | DOI Listing |
J Clin Immunol
December 2024
Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy.
Background: Activated Phosphoinositide 3-Kinase (PI3K) δ Syndrome (APDS), an inborn error of immunity due to upregulation of the PI3K pathway, leads to recurrent infections and immune dysregulation (lymphoproliferation and autoimmunity).
Methods: Clinical and genetic data of 28 APDS patients from 25 unrelated families were collected from fifteen Italian centers.
Results: Patients were genetically confirmed with APDS-1 (n = 20) or APDS-2 (n = 8), with pathogenic mutations in the PIK3CD or PIK3R1 genes.
Cell Signal
December 2024
Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan 750021, China; School of Life Sciences, Ningxia University, Yinchuan 750021, China. Electronic address:
Objective: Polycystic ovary syndrome (PCOS) is a metabolic and endocrine disease that entails dysregulated ovulation, hyperandrogenism, and polycystic ovaries. While Wnt5a has been suggested to play key roles in follicular development and female fertility under normal conditions, its functions in the context of PCOS have yet to be established. This study was thus designed to explore the impact of Wnt5a on ovarian granulosa cell autophagy in PCOS, providing in vitro evidence in support of its role in this setting.
View Article and Find Full Text PDFInt Immunopharmacol
December 2024
Hepatology Diagnosis and Treatment Center & Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China. Electronic address:
Cuproptosis is crucial in the development of various liver diseases, yet its involvement in alcoholic liver disease (ALD) remains poorly understood. In this study, we screened cuproptosis-related genes (CRGs) regulating ALD and explored their potential molecular mechanisms. Bioinformatic methods were employed to screen CRGs in ALD, analyze their functional enrichment, signaling pathways, transcriptional regulation, relationship with the immune microenvironment and pathogenic genes, and corresponding single nucleotide polymorphism pathogenic regions, and construct transcription factor-miRNA-mRNA networks.
View Article and Find Full Text PDFClin Genitourin Cancer
November 2024
Ankara University School of Medicine, Department of Medical Oncology, Ankara, Turkey; Ankara University Cancer Institute, Ankara, Turkey. Electronic address:
Introduction: Despite the rapid evolution in management of metastatic renal cell carcinoma (mRCC) over the past decade, challenges remain in accessing new therapies in some parts of the world. Despite therapeutic advancements, attrition rates remain persistently high. This study aims to assess the treatment patterns and attrition rates of patients with mRCC in oncology clinics across Turkey.
View Article and Find Full Text PDFCell Mol Life Sci
December 2024
Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
Cell metabolism is crucial for orchestrating the differentiation and function of regulatory T cells (Tregs). However, the underlying mechanism that coordinates cell metabolism to regulate Treg activity is not completely understood. As a pivotal molecule in lipid metabolism, the role of SHIP-1 in Tregs remains unknown.
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