Article
Biochemistry & Molecular Biology
Angelica Ferro, Dafni Graikioti, Emre Gezer, Constantinos M. M. Athanassopoulos, Muriel Cuendet
Summary: Although proteasome inhibitors have been used as the main treatment for multiple myeloma, patients often relapse and become resistant to drugs. Combining proteasome and histone deacetylase inhibitors has been found to be more effective, as it enhances anti-myeloma activity and improves patient outcomes. Hybrid molecules that combine the pharmacophores of entinostat and bortezomib have been synthesized and shown to have strong antiproliferative activity in multiple myeloma cells, including those resistant to bortezomib, as well as inhibiting histone deacetylase and proteasome activity.
Article
Hematology
Ting Du, Yan Song, Arghya Ray, Xueping Wan, Yao Yao, Mehmet K. Samur, Chen Shen, Johany Penailillo, Tomasz Sewastianik, Yu-Tzu Tai, Mariateresa Fulciniti, Nikhil C. Munshi, Hao Wu, Ruben D. Carrasco, Dharminder Chauhan, Kenneth C. Anderson
Summary: Rpn10 is highly expressed in MM cells and its inhibition can decrease MM cell viability by triggering protein accumulation, cell cycle arrest, and apoptosis. Additionally, inhibiting Rpn10 can increase autophagy, antigen presentation, and activate CD4(+) T and natural killer cells.
Review
Oncology
Philip Weir, David Donaldson, Mary Frances McMullin, Lisa Crawford
Summary: Multiple myeloma is a common blood cancer that affects plasma cells in bone marrow. Despite improvements in treatment options, drug resistance remains a challenge. This review discusses the metabolic changes in multiple myeloma and the development of resistance to proteasome inhibitors, and explores potential therapeutic interventions.
Article
Oncology
Dong Wu, Jiyu Miao, Jinsong Hu, Fangmei Li, Dandan Gao, Hongli Chen, Yuandong Feng, Ying Shen, Aili He
Summary: The study utilized weighted gene co-expression network analysis to investigate the gene expression changes from normal plasma cells to malignant profiling PC, revealing abnormal gene expression mainly focused on the proteasome; PSMB7 was identified as the key gene associated with MM disease progression and drug resistance, with higher expression potentially leading to shorter survival time.
FRONTIERS IN ONCOLOGY
(2021)
Review
Oncology
Tina Paradzik, Cecilia Bandini, Elisabetta Mereu, Maria Labrador, Elisa Taiana, Nicola Amodio, Antonino Neri, Roberto Piva
Summary: Recent investigations are exploring novel combination strategies that could overcome drug resistance and broaden the applicability of proteasome inhibitors (PIs) to other hematological malignancies and solid tumors.
Article
Biochemistry & Molecular Biology
Alessandro Allegra, Claudia Petrarca, Mario Di Gioacchino, Marco Casciaro, Caterina Musolino, Sebastiano Gangemi
Summary: Raised oxidative stress and abnormal redox status are typical features of multiple myeloma cells. Understanding the mechanisms that regulate the relationship between neoplastic cells and redox homeostasis can help identify new therapeutic targets for anti-myeloma drugs and improve treatment effectiveness.
Article
Cell Biology
Minxia Liu, Yinyin Wang, Juho J. Miettinen, Romika Kumari, Muntasir Mamun Majumder, Ciara Tierney, Despina Bazou, Alun Parsons, Minna Suvela, Juha Lievonen, Raija Silvennoinen, Pekka Anttila, Paul Dowling, Peter O'Gorman, Jing Tang, Caroline A. Heckman
Summary: The S100 family members play a potential important role in the development of MM and resistance to established myeloma drugs, especially in the 1q21 chromosome region.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Chemistry, Medicinal
Angelica Ferro, Evangelia Pantazaka, Constantinos M. M. Athanassopoulos, Muriel Cuendet
Summary: Despite being an incurable disease, multiple myeloma (MM) can benefit from combined and targeted therapies, which have shown a decrease in drug resistance and an improvement in overall survival. Histone deacetylases (HDACs) play a crucial role in cancer treatment, including MM, and combining HDAC inhibitors with other regimens is of great interest. Recent advancements include the development of dual-inhibitor entities, which may reduce therapeutic doses and the risk of drug resistance.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Multidisciplinary Sciences
Xiuxiu Lu, Venkata R. Sabbasani, Vasty Osei-Amponsa, Christine N. Evans, Julianna C. King, Sergey G. Tarasov, Marzena Dyba, Sudipto Das, King C. Chan, Charles D. Schwieters, Sulbha Choudhari, Caroline Fromont, Yongmei Zhao, Bao Tran, Xiang Chen, Hiroshi Matsuo, Thorkell Andresson, Raj Chari, Rolf E. Swenson, Nadya I. Tarasova, Kylie J. Walters
Summary: The authors have identified and characterized XL5, a lead compound that binds to the N-terminal Pru domain of human Rpn13 (hRpn13), solved the NMR structure of XL5-ligated hRpn13 Pru, and developed XL5-PROTACs that preferentially target an identified hRpn13 Pru fragment present in multiple myeloma cells.
NATURE COMMUNICATIONS
(2021)
Article
Pharmacology & Pharmacy
Jaydeep K. Srimani, Paul M. Diderichsen, Michael J. Hanley, Richard Labotka, Neeraj Gupta
Summary: Ixazomib has been approved for maintenance therapy in multiple myeloma patients, with similar progression-free survival benefits seen across different exposure levels. Higher exposures were associated with increased probabilities of maintaining complete response and experiencing certain adverse events, while exposure did not predict hematological adverse events and peripheral neuropathy. Lower apparent clearance values were correlated with a reduced likelihood of escalating the dose to 4 mg. The dose titration approach balanced patient benefit and risk, maximizing the fraction of patients who benefited from the higher dose.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Multidisciplinary Sciences
Mengmeng Dong, Jinna Zhang, Xiaoyan Han, Jingsong He, Gaofeng Zheng, Zhen Cai
Summary: This study retrospectively analyzed clinical data of 155 MM patients and found that baseline PN was age-related, leading to more severe BiPN during bortezomib induction therapy and worse PN outcome after induction therapy. MM patients with baseline PN also had worse PFS and OS.
SCIENTIFIC REPORTS
(2022)
Article
Cell Biology
Katarina Chroma, Zdenek Skrott, Jan Gursky, Jaroslav Bacovsky, Pavel Moudry, Tereza Buchtova, Martin Mistrik, Jiri Bartek
Summary: Despite various therapeutic modalities, multiple myeloma remains incurable with low treatment success rate. The common treatment targeting proteasome often leads to drug resistance. In this study, the authors propose a novel proteasome-like inhibitor agent called CuET formed in vivo and in vitro from a known drug, disulfiram. They demonstrate the effectiveness of CuET in killing different resistant forms of multiple myeloma cells, including those resistant to common anti-myeloma drugs. Furthermore, CuET can overcome another form of treatment resistance based on reduced proteasome load. The findings suggest that repurposing disulfiram in combination with copper supplementation could offer a promising treatment option for relapsed and therapy-resistant multiple myeloma patients.
CELL DEATH & DISEASE
(2022)
Letter
Oncology
Seiichi Okabe, Yuko Tanaka, Akihiko Gotoh
Summary: The treatment of multiple myeloma has been improved with the introduction of new drugs, but relapse is still common. Hypoxia plays a crucial role in the bone marrow microenvironment. Inhibitors of PFKFB3 and PFKFB4 show potential in inhibiting myeloma cell growth and enhancing cytotoxicity. Combination treatment with proteasome inhibitors and PFKFB inhibitors has shown enhanced cytotoxic effects.
BIOMARKER RESEARCH
(2022)
Review
Oncology
Yang Bai, Xing Su
Summary: Proteasome inhibitors (PIs) have been crucial therapies for myeloma patients, targeting the overstressed 26S proteasome involved in the disease pathogenesis. However, the major limitation in PI therapy lies in the acquisition of resistance, despite recent advancements in clinical antimyeloma treatment.
ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Zhen Hua, Rongfang Wei, Mengjie Guo, Zigen Lin, Xichao Yu, Xinying Li, Chunyan Gu, Ye Yang
Summary: This study highlights the role of the YTHDF2/STAT5A/MAP2K2/p-ERK axis in the proliferation of multiple myeloma (MM), and targeting YTHDF2 may be a promising therapeutic strategy.
Article
Cell Biology
Patrick Nylund, Alba Atienza Parraga, Jakob Haglof, Elke De Bruyne, Eline Menu, Berta Garrido-Zabala, Anqi Ma, Jian Jin, Fredrik Oberg, Karin Vanderkerken, Antonia Kalushkova, Helena Jernberg-Wiklund
Summary: Sensitivity to EZH2 inhibition in human multiple myeloma cell lines is associated with a specific metabolic and gene expression profile post-treatment, including dysregulation of genes involved in methionine cycling.
CELL DEATH & DISEASE
(2021)
Review
Immunology
Ken Maes, Anna Mondino, Juan Jose Lasarte, Xabier Agirre, Karin Vanderkerken, Felipe Prosper, Karine Breckpot
Summary: Cancer cells can evade the immune system through epigenetic alterations, but epigenetic modulating agents have the potential to restore immunological fitness and overcome peripheral tolerance to transformed cells. By acting on both cancer cells and immune cells, EMAs represent interesting strategies for combinatorial therapies.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Vartika Bisht, Katrina Nash, Yuanwei Xu, Prasoon Agarwal, Sofie Bosch, Georgios V. Gkoutos, Animesh Acharjee
Summary: This study utilized public omics data sets to investigate potential associations between microbiome, metabolome, bulk transcriptomics and single cell RNA sequencing datasets, identifying multiple potential interactions and key genes involved in colorectal cancer pathogenesis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Neerada Meenakshi Warrier, Prasoon Agarwal, Praveen Kumar
Summary: This study focused on investigating gene expression in GBM and found that EOMES, BDNF, HLA-A, and PECAM1 are associated with BIRC5 and CXCR4, with potential implications for stemness and immunology. This has important implications for advancing our understanding of cancer cell stemness characteristics and immune responses.
Article
Biochemistry & Molecular Biology
Mohamad-Reza Aghanoori, Prasoon Agarwal, Evan Gauvin, Raghu S. Nagalingam, Raiza Bonomo, Vinith Yathindranath, Darrell R. Smith, Yan Hai, Samantha Lee, Corinne G. Jolivalt, Nigel A. Calcutt, Meaghan J. Jones, Michael P. Czubryt, Donald W. Miller, Vernon W. Dolinsky, Virginie Mansuy-Aubert, Paul Fernyhough
Summary: Aberrant insulin-like growth factor 1 (IGF-1) signaling may be associated with the development of neurodegenerative disorders, and the role of endogenous IGF-1 in neuroprotection is not well established. In this study, high expression of IGF-1 was found in non-peptidergic neurons and satellite glial cells of dorsal root ganglia, and bidirectional transport of IGF-1 along sensory nerves was observed. However, IGF-1 gene expression was reduced in diabetic rats and mice, and this suppression could contribute to neuropathy. CEBP beta overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were affected by IGF-1.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Cardiac & Cardiovascular Systems
Mateusz M. Tomczyk, Kyle G. Cheung, Bo Xiang, Nahid Tamanna, Ana L. Fonseca Teixeira, Prasoon Agarwal, Stephanie M. Kereliuk, Victor Spicer, Ligen Lin, Jason Treberg, Qiang Tong, Vernon W. Dolinsky
Summary: The study found that SIRT3 expression can attenuate doxorubicin-induced changes in cardiac structure and function by preventing the acetylation of mitochondrial proteins, suggesting SIRT3 as a potential therapeutic target for mitigating doxorubicin-induced dilated cardiomyopathy.
CIRCULATION-HEART FAILURE
(2022)
Article
Immunology
Lien De Beck, Robin Maximilian Awad, Veronica Basso, Noelia Casares, Kirsten De Ridder, Yannick De Vlaeminck, Alessandra Gnata, Cleo Goyvaerts, Quentin Lecocq, Edurne San Jose-Eneriz, Stefaan Verhulst, Ken Maes, Karin Vanderkerken, Xabier Agirre, Felipe Prosper, Juan Jose Lasarte, Anna Mondino, Karine Breckpot
Summary: Combination therapies hold promise for improving the clinical response rates of malignant skin cancer, particularly melanoma. In this study, a dual inhibitor of histone methyltransferase G9a and DNA methyltransferases (DNMTs) was found to induce tumor cell cycle arrest and apoptosis, promote immune cell infiltration, and increase the efficacy of TCR-redirected T cell and dendritic cell vaccination in a preclinical melanoma model.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Neerada Meenakshi Warrier, Ramesh Kumar Krishnan, Vijendra Prabhu, Raghu Chandrashekhar Hariharapura, Prasoon Agarwal, Praveen Kumar
Summary: This study identifies survivin as a significant biomarker for glioblastoma multiforme cancer stem cells (GSCs) and demonstrates its importance in stemness, cancer progression, and therapy resistance.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Philip Vlummens, Stefaan Verhulst, Kim De Veirman, Anke Maes, Eline Menu, Jerome Moreaux, Hugues De Boussac, Nicolas Robert, Elke De Bruyne, Dirk Hose, Fritz Offner, Karin Vanderkerken, Ken Maes
Summary: In this study, bio-informatic tools were used to identify novel targets associated with high-risk myeloma. Protein arginine methyltransferase 5 (PRMT5) was identified as a promising target. The PRMT5 inhibitor EPZ015938 effectively reduced the growth of myeloma cells and induced apoptosis. PRMT5 was found to be involved in regulating alternative splicing, DNA repair, and PI3K/mTOR signaling, and was associated with important genes in MM disease. These findings suggest that PRMT5 could be a potential therapeutic target for myeloma.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Oncology
Anna Borgenvik, Karl O. Holmberg, Sara Bolin, Miao Zhao, Vasil Savov, Gabriela Rosen, Sonja Hutter, Alexandra Garancher, Aldwin Suryo Rahmanto, Tobias Bergstrom, Thale Kristin Olsen, Oliver J. Mainwaring, Damiana Sattanino, Annemieke D. Verbaan, Jessica M. Rusert, Anders Sundstrom, Mar Ballester Bravo, Yonglong Dang, Amelie S. Wenz, Stacey Richardson, Grammatiki Fotaki, Rebecca M. Hill, Adrian M. Dubuc, Antonia Kalushkova, Marc Remke, Matko Cancer, Helena Jernberg-Wiklund, Geraldine Giraud, Xingqi Chen, Michael D. Taylor, Olle Sangfelt, Steven C. Clifford, Ulrich Schueller, Robert J. Wechsler-Reya, Holger Weishaupt, Fredrik J. Swartling
Summary: SOX9 facilitates therapy escape and recurrence in medulloblastoma by temporally inhibiting MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
Article
Endocrinology & Metabolism
Prasoon Agarwal, Brandy A. Wicklow, Allison B. Dart, Nikho A. Hizon, Elizabeth A. C. Sellers, Jonathan M. McGavock, Charlotte P. J. Talbot, Mario A. Fonseca, Wayne Xu, James R. Davie, Meaghan J. Jones, Animesh Acharjee, Vernon W. Dolinsky
Summary: We identified DNA methylation changes and serum metabolites associated with T2D in adolescents, suggesting their potential significance in gene expression and metabolism control.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Oncology
Robbe Heestermans, Wouter De Brouwer, Ken Maes, Isabelle Vande Broek, Freya Vaeyens, Catharina Olsen, Ben Caljon, Ann De Becker, Marleen Bakkus, Rik Schots, Ivan Van Riet
Summary: This study found that circulating cell-free DNA (cfDNA) is the preferred circulating biomarker for genetic characterization in multiple myeloma (MM), providing additional information compared to standard bone marrow analysis. Blood-derived liquid biopsies offer a more comprehensive approach to evaluate the genetic heterogeneity of the tumor.
Article
Biochemistry & Molecular Biology
Prasoon Agarwal, Aleksandra Glowacka, Loay Mahmoud, Wesam Bazzar, Lars-Gunnar Larsson, Mohammad Alzrigat
Summary: Amplification of the MYCN oncogene in neuroblastoma is associated with high-risk disease and poor prognosis. This study reveals that MYCN-amplified neuroblastoma cells have reduced expression of genes involved in NOTCH receptor processing, axoneme assembly, and membrane protein proteolysis. Genes encoding gamma-secretase complex subunits, known for their role in NOTCH signaling, are down-regulated in MYCN-amplified neuroblastoma. Depletion of MYCN or inhibition of gamma-secretase activity restores the expression of gamma-secretase and NOTCH-target genes. This study provides insight into the molecular mechanisms underlying MYCN's contribution to high-risk neuroblastoma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Antonia Kalushkova, Patrick Nylund, Alba Atienza Parraga, Andreas Lennartsson, Helena Jernberg-Wiklund
Summary: Aberrant DNA methylation, dysregulation of chromatin-modifying enzymes, and microRNAs play crucial roles in haematological malignancies by affecting chromatin accessibility and transcriptional output. The interplay between epigenomic alterations and the cellular metabolome may lead to the development of novel treatments and biomarkers for cancer.