The SAR analysis of dietary polyphenols and their antagonistic effects on bortezomib at physiological concentrations DOI Creative Commons

Trương Thị Bạch Vân,

Hsun‐Shuo Chang, Ho‐Cheng Wu

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: July 25, 2024

Background: Bortezomib (BTZ), a primary treatment for MM, but its effectiveness can be reduced by interactions with vicinal diol moieties (VDMs) in polyphenols. Despite this, it’s debated whether BTZ therapy necessitates avoiding polyphenol-rich products, given the low bioavailability of Additionally, it remains unclear structure polyphenols contributes to their antagonism. Therefore, our study aims unravel structure-activity relationship dietary and antagonism at daily diet-achievable physiological concentrations. Methods: We assessed antagonistic effects 25 against using cell viability assays RPMI 8226 cells. ChemGPS-NP helped analyze structural similarity. long-term cytotoxicity evaluated these physiologically relevant Results: By assays, we found positive correlation between number VDMs gallotannins Moreover, origin configuration VDMs, rather than total VDM concentration, play pivotal role combined gallotannins. analysis indicated that aromaticity C-3 hydroxyl group flavonoids’ C-rings enhance Finally, reveal gallic acid (GA), epigallocatechin (EGC), gallate (EGCG), concentrations—attainable through tea consumption—significantly synergistically antagonize BTZ. Conclusion: Due potential reduce BTZ, is advisable MM patients undergoing consumption foods high VDM-containing

Language: Английский

miRNAs driving diagnosis, progression, and drug resistance in multiple myeloma DOI
Mohamed A. Elkady,

Amr Mohamed Yehia,

Elsayed G.E. Elsakka

et al.

Pathology - Research and Practice, Journal Year: 2023, Volume and Issue: 248, P. 154704 - 154704

Published: July 22, 2023

Language: Английский

Citations

28
Ubiquitin–proteasome system as a target for anticancer treatment—an update DOI
Yeon‐Jung Kim, Yeonjoo Lee,

H. Y. Shin

et al.

Archives of Pharmacal Research, Journal Year: 2023, Volume and Issue: 46(7), P. 573 - 597

Published: July 1, 2023

Language: Английский

Citations

28
ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway DOI Open Access

Chang-Hoon Lim,

Xue-Quan Fang,

Hyeji Kang

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2768 - 2768

Published: Feb. 27, 2024

Ubiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to drugs, known as chemoresistance, by acquiring multidrug resistance, resulting in poor clinical outcomes patients with cancer. However, the chemoresistance cancer USP7i (P22077 and P5091) mechanisms overcome it have not yet been investigated. In present study, we generated human acquired resistance USP7i-induced cell death. Gene expression profiling showed that heat stress response (HSR)- unfolded protein (UPR)-related genes were largely upregulated USP7i-resistant cells. Biochemical studies induced phosphorylation activation shock transcription factor 1 (HSF1), mediated endoplasmic reticulum (ER) kinase R-like ER (PERK) signaling pathway. Inhibition HSF1 PERK significantly sensitized cytotoxicity. Our study demonstrated stress–PERK axis is responsible for USP7i, inhibiting potential strategy improving efficacy USP7i.

Language: Английский

Citations

4
Different Strategies to Overcome Resistance to Proteasome Inhibitors—A Summary 20 Years after Their Introduction DOI Open Access
Paweł Tyrna, Grzegorz Procyk, Łukasz Szeleszczuk

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8949 - 8949

Published: Aug. 16, 2024

Proteasome inhibitors (PIs), bortezomib, carfilzomib, and ixazomib, are the first-line treatment for multiple myeloma (MM). They inhibit cytosolic protein degradation in cells, which leads to accumulation of misfolded malfunctioned proteins cytosol endoplasmic reticulum, resulting cell death. Despite being a breakthrough MM therapy, malignant cells develop resistance PIs via different mechanisms. Understanding these mechanisms drives research toward new anticancer agents overcome PI resistance. In this review, we summarize mechanism action how adapt drugs Finally, explore present strategies interfere with The include ubiquitin-proteasome system, drug efflux inhibitors, autophagy disruption, targeting stress response mechanisms, affecting survival cycle regulators, bone marrow microenvironment modulation, immunotherapy. We list potential pharmacological targets examined vitro, vivo, clinical studies. Some have already provided clinicians anti-MM medications, such as panobinostat selinexor. hope that further exploration subject will broaden range therapeutic options improve patient outcomes.

Language: Английский

Citations

4
Prognostic Value of PSMB5 and Correlations with LC3II and Reactive Oxygen Species Levels in the Bone Marrow Mononuclear Cells of Bortezomib-Resistant Multiple Myeloma Patients DOI Creative Commons

Eva Plakoula,

Georgios Kalampounias,

Spyridon Alexis

et al.

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(1), P. 32 - 32

Published: Jan. 6, 2025

Proteasome inhibitors (PIs) constitute the most common type of induction treatment for multiple myeloma. Interactions between proteasome, autophagy, and reactive oxygen species (ROS) have been shown in past, thus emphasizing need a better understanding underlying pathophysiology. For this study, bone marrow mononuclear cells from 110 myeloma patients were collected at different disease stages. PSMB5 LC3I/II protein levels determined using Western blot, proteasome proteolytic activity (PPA) with spectrofluorometry, ROS flow cytometry. accumulation was found to diminish after PI (p-value = 0.014), same pattern observed PPA < 0.001). Conversely, LC3II elevated both remission relapse compared baseline 0.041). Patients lower than 1.06 units had longer disease-free survival those values above (12.0 ± 6.7 vs. 36 12.1 months; p-value Median plasma significantly higher 0.001), implying poor prognosis. Overall, post-treatment reduction could indicate shift proteasomal autophagic degradation as main proteostatic mechanism, explaining resistance. The oxidative stress PI-treated possibly serve an additional compensatory mechanism.

Language: Английский

Citations

0
Comparative Analysis of Acquired Resistance to Bortezomib in Prostate Cancer Cells Using Proteomic and Bioinformatic Tools DOI Creative Commons
Semih Şeker,

Betül Şahin,

Azmi Yerlikaya

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(1)

Published: Jan. 1, 2025

Chemotherapy is a potent tool against cancer, but drug resistance remains major obstacle. To combat this, understanding the molecular mechanisms behind in cancer cells and protein expression changes driving these crucial. Targeting Ubiquitin-Proteasome System (UPS) has proven effective treating multiple myeloma shows promise for solid tumours. Despite initial success with proteasome inhibitor bortezomib, acquired soon after treatment poses significant challenge to its efficacy. In this study, we explored proteins potentially involved bortezomib using label-free nLC-MS/MS proteomic analysis. The investigation revealed 299 notable differences levels bortezomib-resistant PC3 prostate cell line. Using bioinformatics tools, illustrated top 10 gene ontology (GO) processes [e.g., translational initiation (p = 5.964E-10), CRD-mediated mRNA stabilisation 1.636E-5), hydrogen ion transmembrane transport 6.46E-5)] 20 KEGG metabolic pathways 7.601E-13), biosynthesis of amino acids 3.834E-12), chemical carcinogenesis-reactive oxygen species 1.891E-4)] REACTOME metabolism 4.182E-21), translation 9.484E-18), Nonsense-Mediated Decay (NMD) 1.829E-8)] PC3-resistant cells. We further refined our results by comparing them globally validated TCGA datasets. correlated identified through analysis tumour aggressiveness nodal metastasis N0 vs. N1 datasets UALCAN portal 37 consistent results. believe that combination chemotherapeutics targeting could be overcoming developed bortezomib.

Language: Английский

Citations

0
PHLPP and LAMP2 predict favorable treatment response and survival in multiple myeloma patients who receive induction treatment with bortezomib DOI
Qingkun Han, Wei Han, Cuiping Li

et al.

Irish Journal of Medical Science (1971 -), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

Language: Английский

Citations

0
Profilin 1 induces drug resistance by downregulating CD138 expression via autophagy in multiple myeloma DOI Creative Commons
Ya Wang, Zhen Dai,

Shengying Xiao

et al.

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 8, 2025

Multiple myeloma (MM), a plasma cell-derived malignant hematological disease, is often treated with bortezomib, highly effective first-generation proteasome inhibitor. However, resistance to bortezomib common occurrence. Profilin 1 (PFN1), cytoskeleton-related gene known promote autophagy in MM, induces this but it unclear why. The aim of study was uncover the molecular mechanisms involved resistance, considering not only PFN1, also CD138, transmembrane proteoglycan that hallmark and MM cells. We detected CD138 PFN1 bone marrow patients immunohistochemically. studied Gene Expression Omnibus (GEO) data found associated autophagy. then evaluated their expression an cell line via western blot analysis, immunofluorescence assay, flow cytometry; constructed PFN1-overexpressing -knockdown lines; ubiquitinated cells both lines. Overexpression or PFN1-induced downregulated expression. Owing stemness CD138− cells, inhibition overexpression reversed as indicated our clonogenic, apoptosis, CCK-8 assays. These results plays important role bortezomib. Targeting autophagic pathways may provide promising therapeutic strategy for overcoming drug MM.

Language: Английский

Citations

0
The oligosaccharyltransferase complex is an essential component of multiple myeloma plasma cells DOI Creative Commons

Hong Phuong Nguyen,

Enze Liu,

Anh Q. Le

et al.

Deleted Journal, Journal Year: 2025, Volume and Issue: 33(2), P. 200964 - 200964

Published: March 8, 2025

Multiple myeloma (MM) is an incurable malignancy characterized by mutated plasma cell clonal expansion in the bone marrow, leading to severe clinical symptoms. Thus, identifying new therapeutic targets for MM crucial. We identified oligosaccharyltransferase (OST) complex as a novel vulnerability cells. Elevated expression of this associated with relapsed, high-risk MM, and poor prognosis. Disrupting OST suppressed growth, induced cell-cycle arrest, apoptosis. Combined inhibition bortezomib synergistically eliminated cells vitro vivo, via suppressing genes related bortezomib-resistant phenotypes. Mechanistically, disruption downregulated pathological pathways (mTORC1 pathway, glycolysis, MYC targets, cycle) TRAIL-mediated Notably, translation was robustly upon inhibiting complex. Collectively, presents target treatment, combining its offers promising approach relapsed patients.

Language: Английский

Citations

0
Bone-on-a-Chip Systems for Hematological Cancers DOI Creative Commons
Gül Kozalak, Ali Koşar

Biosensors, Journal Year: 2025, Volume and Issue: 15(3), P. 176 - 176

Published: March 9, 2025

Hematological malignancies originating from blood, bone marrow, and lymph nodes include leukemia, lymphoma, myeloma, which necessitate the use of a distinct chemotherapeutic approach. Drug resistance frequently complicates their treatment, highlighting need for predictive tools to guide therapeutic decisions. Conventional 2D/3D cell cultures do not fully encompass in vivo criteria, translating disease models mice humans proves challenging. Organ-on-a-chip technology presents an avenue surmount genetic disparities between species, offering precise design, concurrent manipulation various types, extrapolation data human physiology. The development bone-on-a-chip (BoC) systems is crucial accurately representing microenvironment, predicting drug responses hematological cancers, mitigating resistance, facilitating personalized interventions. BoC modeling cancers research can intricate designs integrated platforms analyzing response simulate scenarios. This review provides comprehensive examination applicable visualizing within context bone. It thoroughly discusses materials pertinent systems, suitable vitro techniques, capabilities clinical settings, potential commercialization.

Language: Английский

Citations

0