Article
Biochemistry & Molecular Biology
Loka Raghu Kumar Penke, Jennifer Speth, Scott Wettlaufer, Christina Draijer, Marc Peters-Golden
Summary: This study evaluated the therapeutic efficacy of the proteasomal inhibitor bortezomib (BTZ) and found that it has antifibrotic actions in lung fibrosis. Surprisingly, these actions are independent of proteasome inhibition and instead mediated by the induction of dual-specificity protein phosphatase 1 (DUSP1).
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Zohreh Jahani, Jamshid Davoodi
Summary: Metformin, an anti-diabetic drug, has a dual effect on breast cancer cell lines by both upregulating and enhancing the degradation of certain proteins during mTORC1 inhibition.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
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
Chemistry, Medicinal
Markus Klein, Michael Busch, Manja Friese-Hamim, Stefano Crosignani, Thomas Fuchss, Djordje Musil, Felix Rohdich, Michael P. Sanderson, Jeyaprakashnarayanan Seenisamy, Gina Walter-Bausch, Ugo Zanelli, Philip Hewitt, Christina Esdar, Oliver Schadt
Summary: Proteasomes are essential components of the ubiquitin-dependent protein degradation pathway, with LMP7 being a subunit of the immunoproteasome. Current pan-proteasome inhibitors nonselectively target LMP7 and other subunits, limiting their therapeutic applicability. Novel amido boronic acids were discovered to selectively inhibit LMP7, leading to the identification of the highly potent and orally available inhibitor M3258, which showed strong antitumor activity in MM models.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Philipp Klingler, Marius Niklaus, Juergen Koessler, Katja Weber, Angela Koessler, Markus Boeck, Anna Kobsar
Summary: In platelets incubated for 24 hours, bortezomib mediates a slight attenuation of inhibitory signaling, associated with facilitated platelet aggregation using threshold agonist concentrations and enhanced adhesion on agonist-coated surfaces.
VASCULAR PHARMACOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Fujun Yang, Qingyu Ji, Rui Liao, Shumeng Li, Yuequan Wang, Xuanbo Zhang, Shenwu Zhang, Haotian Zhang, Qiming Kan, Jin Sun, Zhonggui He, Bingjun Sun, Cong Luo
Summary: This study presents a facile dual-drug nanoassembly that enhances the efficacy of photodynamic therapy by inhibiting the proteasome. The engineered nanoassembly demonstrates multiple advantages, including simple fabrication, high drug co-loading efficiency, flexible dose adjustment, and favorable stability and enrichment.
CHINESE CHEMICAL LETTERS
(2022)
Review
Biochemistry & Molecular Biology
Jianhao Liu, Ruogang Zhao, Xiaowen Jiang, Zhaohuan Li, Bo Zhang
Summary: Bortezomib is a proteasome inhibitor that has been approved for the treatment of multiple myeloma and other hematological cancers. However, its limited specificity, poor permeability, and low bioavailability hinder its applications. Recent research has focused on the development of BTZ-based drug delivery systems.
Article
Oncology
Tian-Yi Jiang, Xiao-Fan Feng, Zheng Fang, Xiao-Wen Cui, Yun-Kai Lin, Yu-Fei Pan, Chun Yang, Zhi-Wen Ding, Yong-Jie Zhang, Ye-Xiong Tan, Hong-Yang Wang, Li-Wei Dong
Summary: This study identified frequent alterations of PTEN in GBC, showing correlation with poor prognosis, and indicated proteasome inhibitor bortezomib as a promising therapeutic agent. Knockdown of PTEN increased bortezomib efficacy, and further evaluation using PDXs supported the utilization of bortezomib in PTEN-deficient GBC. Mechanistically, PTEN inhibited proteasome activity and bortezomib sensitivity through ARE-dependent transcriptional regulation, with involvement of the BACH1 transcriptional suppressor.
Article
Biochemistry & Molecular Biology
Kyota Ishii, Mayuko Hido, Misaki Sakamura, Nantiga Virgona, Tomohiro Yano
Summary: This study demonstrated that T3, TOS, and T3E enhance the sensitivity of the proteasome inhibitor BTZ in solid cancers by modulating the activity of NFE2L1. Inactivation of NFE2L1 by T3, TOS, and T3E is essential to potentiate the cytotoxic effect of BTZ in solid cancers.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cardiac & Cardiovascular Systems
Hericka Bruna Figueiredo Galvao, Quynh Nhu Dinh, Jordyn M. Thomas, Flavia Wassef, Henry Diep, Alex Bobik, Christopher G. Sobey, Grant R. Drummond, Antony Vinh
Summary: The effect of reducing antibody-secreting cells (ASCs) on angiotensin II-induced hypertension was tested using the proteasome inhibitor bortezomib. ASCs and antibody levels were decreased, but hypertension was not affected.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2023)
Review
Immunology
Naeemeh Khalesi, Shahla Korani, Mitra Korani, Thomas P. Johnston, Amirhossein Sahebkar
Summary: Autoimmune diseases are conditions where the immune system cannot distinguish self from non-self, leading to tissue injury. The proteasome inhibitor bortezomib has shown effectiveness in treating patients with ADs resistant to conventional therapies.
INFLAMMOPHARMACOLOGY
(2021)
Article
Materials Science, Biomaterials
Liqin Cao, Huiyao Gu, Zhaowenbing Zhang, Enfan Zhang, Jiang Chang, Zhen Cai
Summary: Multiple myeloma is a common hematologic malignancy and the current treatment with Bortezomib often leads to drug resistance and side effects. The study shows that calcium silicate enhances the anti-myeloma effect of Bortezomib and suggests that this combination could be a promising strategy to overcome drug resistance in multiple myeloma.
JOURNAL OF MATERIALS CHEMISTRY B
(2023)
Article
Oncology
Anup Joseph Devasia, Guido Lancman, A. Keith Stewart
Summary: The ongoing therapeutic revolution in multiple myeloma care can be traced back to the discovery of the clinical effectiveness of thalidomide and the emergence of proteasome inhibitors. These discoveries have significantly improved the care and survival of patients with multiple myeloma.
Article
Oncology
Diana Zagirova, Rebecca Autenried, Morgan E. Nelson, Khosrow Rezvani
Summary: The clinical efficacy of proteasome inhibitors in solid tumor treatment is lower due to the functional and structural heterogeneity of proteasomes. Ongoing trials are exploring compound and novel proteasome inhibitors for solid tumors. Further research is needed to clarify the effects of proteasome inhibitors on different proteasomes in cancer cells.
Article
Biochemistry & Molecular Biology
Ethan L. L. Morgan, Tiffany Toni, Ramya Viswanathan, Yvette Robbins, Xinping Yang, Hui Cheng, Sreenivasulu Gunti, Angel Huynh, Anastasia L. L. Sowers, James B. B. Mitchell, Clint T. T. Allen, Zhong Chen, Carter Van Waes
Summary: TNF alpha is a key mediator of immune, chemotherapy and radiotherapy-induced cytotoxicity, but several cancers display resistance to TNF alpha due to activation of the NF kappa B pro-survival pathway. In this study, we found that the expression of USP14, a proteasome-associated deubiquitinase, is increased in HNSCC and correlates with worse progression free survival. Inhibition or depletion of USP14 inhibited the proliferation and survival of HNSCC cells and reduced NF kappa B activity. Furthermore, we showed that the inhibitor b-AP15 sensitized HNSCC cells to TNF alpha-mediated cell death and radiation-induced cell death, and delayed tumor growth in vivo.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Pharmacology & Pharmacy
Felicitas Stoll, Antje Blank, Gerd Mikus, David Czock, Kathrin Foerster, Simon Hermann, Katja Guemues, Amin Muhareb, Simone Hummler, Max Sauter, Johanna Weiss, Juergen Burhenne, Walter E. Haefeli
Summary: The study results indicate that proton pump inhibitors do not affect the absorption of hydroxychloroquine, suggesting that coadministration of proton pump inhibitors with hydroxychloroquine may not affect the bioavailability of hydroxychloroquine.
CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT
(2022)
Article
Oncology
Romain Sigaud, Lisa Roesch, Charlotte Gatzweiler, Julia Benzel, Laura von Soosten, Heike Peterziel, Florian Selt, Sara Najafi, Simay Ayhan, Xenia F. Gerloff, Nina Hofmann, Isabel Buedenbender, Lukas Schmitt, Kathrin Foerster, Juergen Burhenne, Walter E. Haefeli, Andrey Korshunov, Felix Sahm, Cornelis M. van Tilburg, David T. W. Jones, Stefan M. Pfister, Deborah Knoerzer, Brent L. Kreider, Max Sauter, Kristian W. Pajtler, Marc Zuckermann, Ina Oehme, Olaf Witt, Till Milde
Summary: The study demonstrates that ulixertinib monotherapy and combination therapies can effectively inhibit pLGG growth, showing promising potential for the treatment of pLGG.
Article
Geriatrics & Gerontology
Annette Eidam, Julian Marji, Petra Benzinger, Kathrin I. I. Foerster, Juergen Burhenne, David Czock, Felicitas Stoll, Antje Blank, Gerd Mikus, Walter E. E. Haefeli, Juergen M. Bauer
Summary: This study aimed to explore the relationship between different frailty assessments and trough plasma concentrations of direct oral anticoagulants in older patients. The results showed that frail participants had 2.48-fold higher drug concentrations compared to robust participants and these concentrations were positively correlated with frailty assessments. This study suggests that frailty may affect the drug exposure of direct oral anticoagulants in older adults.
Article
Oncology
Margaux Fresnais, Ina Jung, Uli B. Klein, Aubry K. Miller, Sevin Turcan, Walter E. Haefeli, Juergen Burhenne, Remi Longuespee
Summary: Monitoring the chemical effects of drugs at their molecular target is important for personalized medicine. However, analyzing these effects can be difficult due to molecular interferences. This study evaluates the use of desorption/ionization mass spectrometry for this purpose.
Article
Toxicology
Julie Nilles, Johanna Weiss, Max Sauter, Walter E. Haefeli, Stephanie Ruez, Dirk Theile
Summary: Compared to standard doses of rifampicin, standard doses of rifabutin have a lower risk of drug-drug interactions. Rifabutin has weaker cellular uptake, less activation of the nuclear receptor, and less impact on gene expression and activity. Additionally, rifabutin is a potent inhibitor of Pgp.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Mareile H. Breithaupt, Evelyn Krohmer, Lenka Taylor, Eva Koerner, Torsten Hoppe-Tichy, Juergen Burhenne, Kathrin I. Foerster, Markus Dachtler, Gerald Huber, Rakesh Venkatesh, Karin Eggenreich, David Czock, Gerd Mikus, Antje Blank, Walter E. Haefeli
Summary: Metamizole acts as a strong inducer of CYP3A, affecting the pharmacokinetics of drugs metabolized via this enzyme. It should be avoided in patients using CYP3A substrate drugs and close monitoring and dose adjustment of comedication are recommended.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2023)
Article
Cardiac & Cardiovascular Systems
Alexander Lenard, Simon A. A. Hermann, Felicitas Stoll, Juergen Burhenne, Kathrin I. I. Foerster, Gerd Mikus, Andreas D. Meid, Walter E. E. Haefeli, Antje Blank
Summary: The study assessed the differential effect of clarithromycin on the pharmacokinetics of edoxaban and a cocktail of factor Xa inhibitors. It was found that clarithromycin increased the exposure of edoxaban and the FXaI cocktail. However, the magnitude of this drug interaction is not clinically relevant.
CARDIOVASCULAR DRUGS AND THERAPY
(2023)
Article
Biochemistry & Molecular Biology
Margaux Fresnais, Siwen Liang, Deniz Seven, Nevena Prodanovic, Julia Sundheimer, Walter E. Haefeli, Juergen Burhenne, Remi Longuespee
Summary: The development and validation of desorption/ionization mass spectrometric assays for drug quantification in tissue sections is crucial for their widespread application in (clinical) pharmacology. Advances in desorption electrospray ionization have demonstrated its usefulness for developing targeted quantification methods that meet validation requirements. Factors such as desorption spot morphology, analytical time, and sample surface need to be considered for successful method development. This study highlights the importance of considering desorption kinetics during DESI analyses, which can help reduce analytical time, verify solvent-based drug extraction methods, and predict feasibility of imaging assays. These findings provide valuable guidance for future development of validated DESI-profiling and imaging methods.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Vanessa Zhu, Juergen Burhenne, Johanna Weiss, Mathias Haag, Ute Hofmann, Matthias Schwab, Stephan Urban, Gerd Mikus, David Czock, Walter E. Haefeli, Antje Blank
Summary: This study investigated the drug-drug interaction potential and pharmacokinetics of high-dose subcutaneous bulevirtide (5 mg twice daily) with OATP1B1 and CYP3A4. The results showed that high-dose bulevirtide had inhibitory effects on OATP1B-mediated uptake of pravastatin, but the extent of inhibition was not clinically relevant. There were also no clinically relevant changes in CYP3A4 activity. Therefore, it is safe to use OATP1B substrate drugs and CYP3A4 substrate drugs without dose adjustment in patients treated with bulevirtide.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Fatima Zahra Marok, Jan-Georg Wojtyniak, Laura Maria Fuhr, Dominik Selzer, Matthias Schwab, Johanna Weiss, Walter Emil Haefeli, Thorsten Lehr
Summary: This study developed a physiologically based pharmacokinetic (PBPK) model to investigate the drug-food interactions (DFIs) and drug-drug interactions (DDIs) potential of ketoconazole and its metabolites. The results showed that the metabolites of ketoconazole have an impact on its DDI potential. Various scenarios were simulated and evaluated, and the best predictive performance was achieved by including all metabolites as reversible inhibitors.
Article
Chemistry, Multidisciplinary
Margaux Fresnais, Ina Jung, Uli B. Klein, Dirk Theile, Siwen Liang, Walter E. Haefeli, Juergen Burhenne, Remi Longuespee
Summary: Quantitative monitoring of biologically active methylation of guanines induced by TMZ is important in glioblastoma research. LC-MS/MS with MRM offers the specificity and sensitivity required for such assays. Here, we present the development of LC-MRM-MS assays for quantifying O6-m2dGO in a TMZ-treated glioblastoma cell line.
Article
Pharmacology & Pharmacy
Amin Muhareb, Antje Blank, Andreas D. Meid, Kathrin I. Foerster, Felicitas Stoll, Juergen Burhenne, Walter E. Haefeli, Gerd Mikus
Summary: This study aimed to determine if microdosed probe drugs for CYP3A and CYP2C19 can reliably predict voriconazole clearance. The results showed that the higher the dose of voriconazole, the lower the clearance of midazolam and omeprazole, and both were linearly correlated with voriconazole clearance. Therefore, microdosed probe drugs accurately described and predicted voriconazole clearance.
CLINICAL PHARMACOKINETICS
(2023)
Review
Biology
Anna Gagliardi, Gzona Bajraktari-Sylejmani, Elisabetta Barocelli, Johanna Weiss, Juan Pablo Rigalli
Summary: Drug-metabolizing enzymes (DMEs) and transporters are crucial for drug efficacy and safety. This article explores the use of extracellular vesicles (EVs) as a less invasive way to estimate the expression and activity of DMEs and transporters in the liver, intestine, and kidney. Preliminary evidence suggests a correlation between EVs and tissue expression, indicating that EVs could potentially be used for precision therapy based on individual biotransformation and excretion capacities.
Meeting Abstract
Oncology
Romain Sigaud, Caroline Hess, Thomas Hielscher, Nadine Winkler, Florian Selt, Daniela Kocher, Leo Nonnenbroich, Diren Usta, Alex Sommerkamp, Isabel Buedenbender, David Capper, Ulrich W. Thomale, Pablo Hernaiz Driever, Michele Simon, Arend Koch, Nada Jabado, Augusto F. Andrade, Netteke Schouten-van Meeteren, Eelco Hoving, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Till Milde