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Pharmaceuticals
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Drug Candidates for the Treatment of Multiple Myeloma
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Drug Candidates for the Treatment of Multiple Myeloma

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 16554

Special Issue Editor

Dr. Akinobu Ota

E-Mail Website
Guest Editor
Department of Biochemistry, Aichi Medical University School of Medicine, Building No 2, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
Interests: cancer treatment; molecular oncology; gene expression; gene editing

Special Issue Information

Dear Colleagues,

Multiple myeloma (MM) is an incurable B cell malignancy caused by the abnormal expansion of bone marrow-derived plasma cells, and gives rise to clinical symptoms including bone pain, anemia, hypercalcemia and patients becoming immunocompromised.

The treatment of patients with MM has much improved during the recent two decades, in which immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies against immune cell surface markers play an important role as novel agents to treat MM.
However, multiple myeloma cells often acquire additional genomic and/or epigenetic changes themselves, and they eventually develop to more malignant types, which potentially exhibit multi-drug resistance and plasma cell leukemia.

Meanwhile, researchers have characterized that MM cells possess a number of common genomic alterations including somatic mutations, chromosomal amplification/deletion, some of which could represent druggable molecular target and certain drug sensitivity to current therapeutics. Due to advances in both genome sequencing and genome editing, an understanding of molecular characteristics of refractory/relapsed MM could be utilized to develop a targeted genomic therapy and novel molecular-targeted strategies, which could lead to improved clinical outcomes in patients with MM.

The journal Pharmaceuticals invites both reviews and original articles scoping on the challenges and opportunities specific to MM. Topics include novel drug candidates, such as molecular-targeted drugs, immunomodulatory drugs, proteasome inhibitors, chimeric antigen receptor T cells, and immune check point inhibitors. Topics also include potent therapeutic strategies, such as combination therapies, for the treatment of relapsed/refractory MM. The collection of manuscripts will be published as a Special Issue of the journal.

Dr. Akinobu Ota
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • multiple myeloma
  • immunomodulatory drugs
  • molecular-targeted therapy
  • CAR-T
  • proteasome inhibitors
  • immune checkpoint inhibitors
  • transplantation
  • relapsed/refractory multiple myeloma
  • drug resistance
  • combination therapy

Published Papers (6 papers)

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Research

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18 pages, 5964 KiB  
Article
Ancistrocladinium A Induces Apoptosis in Proteasome Inhibitor-Resistant Multiple Myeloma Cells: A Promising Therapeutic Agent Candidate
by Daniela Brünnert, Raina Seupel, Pankaj Goyal, Matthias Bach, Heike Schraud, Stefanie Kirner, Eva Köster, Doris Feineis, Ralf C. Bargou, Andreas Schlosser, Gerhard Bringmann and Manik Chatterjee
Pharmaceuticals 2023, 16(8), 1181; https://doi.org/10.3390/ph16081181 - 18 Aug 2023
Cited by 2 | Viewed by 1568
Abstract
The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma [...] Read more.
The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)
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18 pages, 2426 KiB  
Article
New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies
by Romina A. Guedes, Jorge H. Grilo, Andreia N. Carvalho, Pedro M. P. Fernandes, Ana S. Ressurreição, Vanessa Brito, Adriana O. Santos, Samuel Silvestre, Eleonora Gallerani, Maria João Gama, Riccardo Gavioli, Jorge A. R. Salvador and Rita C. Guedes
Pharmaceuticals 2023, 16(8), 1096; https://doi.org/10.3390/ph16081096 - 02 Aug 2023
Cited by 2 | Viewed by 1208
Abstract
Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin–proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still [...] Read more.
Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin–proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of proteasome inhibitors with anticancer activity, aiming to overcome the limitations of the existing proteasome inhibitors. Thus, a structure-based virtual screening protocol was developed using the structure of the human 20S proteasome, and 246 compounds from virtual databases were selected for in vitro evaluation, namely proteasome inhibition assays and cell viability assays. Compound 4 (JHG58) was shortlisted as the best hit compound based on its potential in terms of proteasome inhibitory activity and its ability to induce cell death (both with IC50 values in the low micromolar range). Molecular docking studies revealed that compound 4 interacts with key residues, namely with the catalytic Thr1, Ala20, Thr21, Lys33, and Asp125 at the chymotrypsin-like catalytic active site. The hit compound is a good candidate for additional optimization through a hit-to-lead campaign. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)
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18 pages, 3573 KiB  
Article
Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications
by Nuria Vilaboa, Juan Antonio Lopez, Marco de Mesa, Clara Escudero-Duch, Natalie Winfield, Melanie Bayford and Richard Voellmy
Pharmaceuticals 2023, 16(4), 616; https://doi.org/10.3390/ph16040616 - 19 Apr 2023
Cited by 1 | Viewed by 1567
Abstract
Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells [...] Read more.
Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells revealed that withaferin A, IHSF058 and IHSF115 caused denaturation of 915, 722 and 991 of 5132 detected cellular proteins, respectively, of which 440 were targeted by all three compounds. Western blots showed that important fractions of these proteins, in some cases approaching half of total protein amounts, unfolded. Relatively indiscriminate covalent modification of target proteins was observed; 1178 different proteins were modified by IHSF058. Further illustrating the depth of the induced proteostasis crisis, only 13% of these proteins detectably aggregated, and 79% of the proteins that aggregated were not targets of covalent modification. Numerous proteostasis network components were modified and/or found in aggregates. Proteostasis disruption caused by the study compounds may be more profound than that mediated by proteasome inhibitors. The compounds act by a different mechanism that may be less susceptible to resistance development. Multiple myeloma cells were particularly sensitive to the compounds. Development of an additional proteostasis-disrupting therapy of multiple myeloma is suggested. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)
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Review

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23 pages, 2249 KiB  
Review
Antibody–Drug Conjugates for Multiple Myeloma: Just the Beginning, or the Beginning of the End?
by Upasana Ray and Robert Z. Orlowski
Pharmaceuticals 2023, 16(4), 590; https://doi.org/10.3390/ph16040590 - 14 Apr 2023
Cited by 5 | Viewed by 3695
Abstract
Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 [...] Read more.
Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved in the advanced setting. Most recently, the bispecific anti-BCMA and T-cell-engaging antibody teclistamab has become available, again for patients with relapsed/refractory disease. Another format into which antibodies can be converted to exert anti-tumor efficacy is as antibody–drug conjugates (ADCs), and belantamab mafodotin, which also targets BCMA, represented the first such agent that gained a foothold in myeloma. Negative results from a recent Phase III study have prompted the initiation of a process for withdrawal of its marketing authorization. However, belantamab remains a drug with some promise, and many other ADCs targeting either BCMA or other plasma cell surface markers are in development and showing potential. This contribution will provide an overview of some of the current data supporting the possibility that ADCs will remain a part of our chemotherapeutic armamentarium against myeloma moving forward, and also highlight areas for future development. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)
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27 pages, 3455 KiB  
Review
Past, Present, and a Glance into the Future of Multiple Myeloma Treatment
by Weam Othman Elbezanti, Kishore B. Challagundla, Subash C. Jonnalagadda, Tulin Budak-Alpdogan and Manoj K. Pandey
Pharmaceuticals 2023, 16(3), 415; https://doi.org/10.3390/ph16030415 - 08 Mar 2023
Cited by 7 | Viewed by 3296
Abstract
Multiple myeloma (MM) is a challenging hematological cancer which typically grows in bone marrow. MM accounts for 10% of hematological malignancies and 1.8% of cancers. The recent treatment strategies have significantly improved progression-free survival for MM patients in the last decade; however, a [...] Read more.
Multiple myeloma (MM) is a challenging hematological cancer which typically grows in bone marrow. MM accounts for 10% of hematological malignancies and 1.8% of cancers. The recent treatment strategies have significantly improved progression-free survival for MM patients in the last decade; however, a relapse for most MM patients is inevitable. In this review we discuss current treatment, important pathways for proliferation, survival, immune suppression, and resistance that could be targeted for future treatments. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)
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22 pages, 2185 KiB  
Review
Review on Bortezomib Resistance in Multiple Myeloma and Potential Role of Emerging Technologies
by Gül Kozalak, İsmail Bütün, Erçil Toyran and Ali Koşar
Pharmaceuticals 2023, 16(1), 111; https://doi.org/10.3390/ph16010111 - 12 Jan 2023
Cited by 8 | Viewed by 4025
Abstract
Multiple myeloma is a hematological cancer type. For its treatment, Bortezomib has been widely used. However, drug resistance to this effective chemotherapeutic has been developed for various reasons. 2D cell cultures and animal models have failed to understand the MM disease and Bortezomib [...] Read more.
Multiple myeloma is a hematological cancer type. For its treatment, Bortezomib has been widely used. However, drug resistance to this effective chemotherapeutic has been developed for various reasons. 2D cell cultures and animal models have failed to understand the MM disease and Bortezomib resistance. It is therefore essential to utilize new technologies to reveal a complete molecular profile of the disease. In this review, we in-depth examined the possible molecular mechanisms that cause Bortezomib resistance and specifically addressed MM and Bortezomib resistance. Moreover, we also included the use of nanoparticles, 3D culture methods, microfluidics, and organ-on-chip devices in multiple myeloma. We also discussed whether the emerging technology offers the necessary tools to understand and prevent Bortezomib resistance in multiple myeloma. Despite the ongoing research activities on MM, the related studies cannot provide a complete summary of MM. Nanoparticle and 3D culturing have been frequently used to understand MM disease and Bortezomib resistance. However, the number of microfluidic devices for this application is insufficient. By combining siRNA/miRNA technologies with microfluidic devices, a complete molecular genetic profile of MM disease could be revealed. Microfluidic chips should be used clinically in personal therapy and point-of-care applications. At least with Bortezomib microneedles, it could be ensured that MM patients can go through the treatment process more painlessly. This way, MM can be switched to the curable cancer type list, and Bortezomib can be targeted for its treatment with fewer side effects. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)
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