Chemogenomics Mapping of Potential Drugs and Targets for Treatment of Multiple Myeloma

2021 ◽  
Author(s):  
Shifan Ma ◽  
Xiang-Qun Xie
Keyword(s):  
Multiple Myeloma ◽  
Gene Signature ◽  
Therapeutic Interventions ◽  
Data Sets ◽  
Diagnostic Biomarkers ◽  
Risk Of Death ◽  
Pathological Mechanism ◽  
Search Data ◽  
Drug Reposition

Abstract Multiple myeloma (MM) is the second common hematological malignancy affecting about 352,000 worldwide. Some subgroups of MM patients still cannot benefit from the currently available anti-MM drugs and therefore are at high risk of death. The pathological mechanism of MM remains to be unraveled. The identification of a global gene signature for MM might lead toward development of novel diagnostics and therapeutic interventions. Here, we identified common differentially expressed genes (DEGs) shared by 30 MM microarray data sets and compared the common DEGs with those induced by genetic or chemical perturbations. We found some potential therapeutic targets for MM treatment, for example RARA, FGFR1, PML, ROR1, SLAMF7, MTDH and Daxx. as modulating them can reverse the MM-induced gene signature. Based on our analysis results, we also predicted and validated some drug reposition, such as Imatinib, Decitabine, Dexamethasone, Vincristine, Paclitaxel, as well as Bortezomib plus Bafilomycin A1 combination for MM treatment by a literature search, data mining, and in vitro bioassays. This study could provide guidance and indications for the development of MM specific diagnostic biomarkers, indication predictors and therapeutic treatment.

scholarly journals IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

2021 ◽  
Author(s):  
Kristin Roseth Aass ◽  
Robin Mjelle ◽  
Martin H. Kastnes ◽  
Synne S. Tryggestad ◽  
Luca M. van den Brink ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Oxidative Phosphorylation ◽  
Plasma Cells ◽  
Inflammatory Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Gene Signature ◽  
Growth And Survival ◽  
Novel Concept

AbstractIL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

scholarly journals miR-217 Is a Useful Diagnostic Biomarker and Regulates Human Podocyte Cells Apoptosis via Targeting TNFSF11 in Membranous Nephropathy

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Jing Li ◽  
Bin Liu ◽  
Hen Xue ◽  
Qiao Qiao Zhou ◽  
Ling Peng
Keyword(s):  
Membranous Nephropathy ◽  
Target Gene ◽  
In Vitro Experiments ◽  
Diagnostic Biomarker ◽  
Diagnostic Biomarkers ◽  
Cutoff Value ◽  
Pathological Mechanism ◽  
Opposite Change ◽  
And Control

Background. MicroRNAs have recently been verified as useful diagnostic biomarkers in various diseases. In this study, we investigated whether miR-217 is a useful diagnostic biomarker and the possible pathological mechanism of miR-217 in this disease. Methods. Patients with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and diabetic nephropathy (DN) and control patients were enrolled in this study. The miR-217 inhibitor and mimics were transfected into human podocyte cells to investigate the pathological mechanism of miR-217 in this disease. Relevant indicators were detected and tested. Results. Compared with control patients, miR-217 was significantly downregulated and TNFSF11 was significantly upregulated in MN. Then, miR-217 had obvious separation between patients with MN and control patients, with an AUC of 0.941, a cutoff value of <750.0 copies/ul, and sensitivity and specificity of 88.9% and 75.9%. In addition, the TNFSF11 was confirmed to be the target gene of miR-217. Finally, in in vitro experiments, the upregulation of miR-217 could decrease the expression of TNFSF11 and not induce human podocyte cells apoptosis; however, the downregulation of miR-217 could bring about an opposite change. Conclusions. miR-217 is a useful diagnostic biomarker and is involved in human podocyte cells apoptosis via targeting TNFSF11 in membranous nephropathy.

Good and Poor Response Gene Expression Signatures to Proteasome Inhibitors Using a Mouse Model of Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1843-1843
Author(s):  
Holly Stessman ◽  
Linda B. Baughn ◽  
Aaron G. Sarver ◽  
Aatif Mansoor ◽  
Tzu G. Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Cell Lines ◽  
Copy Number ◽  
Research Funding ◽  
Proteasome Inhibitors ◽  
Gene Signature ◽  
Mouse Tumor ◽  
Tumor Cell Lines

Abstract Abstract 1843 The proteasome inhibitor bortezomib (Bz) has been used extensively and with much success in the treatment of multiple myeloma (MM) patients; however, patients eventually relapse, many as non-responders to subsequent treatments with Bz making drug resistance a significant problem. Here we utilized cell lines created using a iMycCa/Bcl-xL transgenic mouse model of MM (Cheung, et al. J Clin Invest (2004) 113: 1763) to identify 1) gene expression signatures of Bz response, 2) differences in gene expression between sensitive and resistant cell lines, and 3) cytogenetic abnormalities associated with Bz sensitive and resistant phenotypes. The iMycCa/Bcl-xL transgenic mice develop plasma cell tumors with 100% penetrance and have shown strikingly strong similarities to human MM by extensive gene expression profiling (GEP), spectral karyotyping and histology (Boylan, et al. Cancer Res (2007) 67: 4069). Six cell lines created from these mice were dose escalated with Bz over approximately six months to create Bz resistant (BzR) cell lines with approximately 5–8 fold increase in IC50 to Bz compared to their sensitive counterparts. The BzR characteristics were stable, as lines grown in the absence of drug for as long as 6 months maintained drug resistance upon subsequent challenge. Notably, BzR lines showed cross resistance to other investigational proteasome inhibitors (MLN9708 and carfilzomib) while maintaining sensitivity to other chemotherapeutic agents (dexamethasone and melphalan), suggesting a common mechanism of emerging resistance to proteasome inhibitors. The results of GEP of these mouse tumor cell lines treated with Bz were compared with a recently published human drug trial where GEP was completed prior to and 48 hours after a “test dose” of Bz was administered to patients (Shaughnessy, et al. Blood (2011), ahead of print). In the mouse tumor cell lines, 116 genes were differentially expressed upon in vitro Bz treatment (p=0.001, ≥1.5 fold change). Between the mouse and human drug response data sets was an overlapping common 27-gene signature (p=1×10−25, Fishers exact test) of Bz-induced expression changes that has not previously been described. Time points were collected in these mouse cell line GEP experiments at 0, 2, 8, 16, and 24 hours after Bz treatment. A comparison of the Bz sensitive and derived BzR lines prior to drug treatment revealed a 50 gene signature (p=0.05, ≥2 fold change) that distinguishes three pairs of sensitive and resistant lines. Gene-set enrichment analyses have revealed significant pathways that are differentially regulated in the sensitive and resistant responses. Additional GEP differences were seen when time course expression patterns were examined from Bz sensitive compared to resistant tumor lines. Thus, GEP signatures that distinguish tumor lethality from resistance were identified both prior to Bz treatment, as well as in the early response to Bz. In addition, array comparative genomic hybridization on 4 pairs of mouse Bz sensitive and established BzR lines revealed not only gross differences in copy number between the differentially responding groups of cells but copy number abnormalities that may be unique to the emerging resistance. Taken together, these data indicate that this model is useful for the identification of good and poor Bz response signatures in MM. These signatures are currently being evaluated in human tumor cells from single agent bortezomib phase II and phase III clinical trials. Because the in vitro adapted tumor mouse lines can be genetically manipulated using lentiviral vectors, this model can be used as a preclinical platform to validate existing gene models with respect to Bz response, something that cannot be done using human patients. Subsequent transfer of manipulated lines into syngeneic, immunocompetent recipients can further test Bz response in vivo presenting a significant advantage of this robust mouse MM model system over other in vitro systems. Disclosures: Stessman: Millennium: The Takeda Oncology Company: Research Funding. Mansoor:Millennium: The Takeda Oncology Company: Research Funding. Janz:Millennium: The Takeda Oncology Company: Research Funding. Van Ness:Millennium: The Takeda Oncology Company: Research Funding.

scholarly journals The Impact of the NOD2/CARD15 Variant (3020insC) and PSMA6 Polymorphism (-8C>G) on the Development and Outcome of Multiple Myeloma

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
S. Zmorzyński ◽  
S. Popek-Marciniec ◽  
W. Styk ◽  
M. Wojcierowska-Litwin ◽  
I. Korszeń-Pilecka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Bone Marrow Cells ◽  
Risk Of Death ◽  
Automated Dna Sequencing ◽  
Increased Risk ◽  
Pcr Rflp ◽  
Relationship Of ◽  
The Impact

Introduction. Multiple myeloma (MM) is a hematological malignancy characterized by genetic variety. The 3020insC variant of the NOD2/CARD15 gene results in the upregulation of proinflammatory cytokines. Chronic inflammation and abnormal function of the proteasome system may lead to MM development. The polymorphism (-8C>G) in the PSMA6 gene affects proteasome activity. The aim of our study was to analyze the possible relationship of NOD/CARD15 and PSMA6 genes with the risk of development and outcome of MM, as well as the sensitivity to bortezomib (proteasome inhibitor) in cell cultures derived from MM patients. Objects and Methods. Genomic DNA from 100 newly diagnosed MM patients and 100 healthy blood donors was analyzed by methods such as PCR-RFLP (for PSMA6 genotyping) and automated DNA sequencing (for NOD2/CARD15 genotyping). In a subgroup of 50 MM patients, nucleated bone marrow cells were treated with bortezomib in vitro. Results. Patients with PSMA6 CG+GG genotypes had higher chances for progressive disease (OR=5.0, 95% CI 1.07-23.16, p=0.05), shorter overall survival taking into account the type of treatment (p=0.039), and increased risk of death due to MM at the level of tendency (OR=4.74, 95% CI 1.02-21.97, p=0.06). The presence of NOD2/CARD15 3020insC decreased the risk of renal dysfunction in MM (OR=0.23, 95% CI 0.07-0.74, p=0.009). The analyzed changes in NOD2/CARD15 and PSMA6 genes did not impact the MM risk. In an in vitro study, bortezomib increased the number of apoptotic cells at 8 nM and 12 nM between wild-type and 3030insC variants of NOD2/CARD15 (p=0.018 and p=0.03, respectively). Conclusion. The presented results suggest a possible impact of PSMA6 CG+GG genotypes on the MM outcome and the association of the NOD2/CARD15 variant with bortezomib in vitro sensitivity.

Microrna-138 Regulates Osteogenic Differentiation and Its Inhibition Presents a Novel Therapeutic Line to Prevent Bone Lytic Lesions in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4483-4483
Author(s):  
Shokichi Tsukamoto ◽  
Karma Salem ◽  
Salomon Manier ◽  
Michaela R. Reagan ◽  
Daisy Huynh ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Osteogenic Differentiation ◽  
Cell Lines ◽  
Research Funding ◽  
Plasma Cells ◽  
Data Sets ◽  
Normal Plasma ◽  
Lytic Lesions

Abstract Introduction The bone marrow (BM) microenvironment in multiple myeloma (MM) plays a pivotal role in tumor growth and bone destructive process. Mesenchymal stromal cells (MSCs) in MM exhibit different genomic and cytokine secretion profiles that ultimately impair their osteogenic differentiation abilities compared to normal MSCs. However, the underlying molecular mechanisms are not fully understood. In the present study, we explored the role of miR-138 in MSCs derived from MM patients (MM-MSCs) and the potential for anti-miR-138 treatment to rescue impaired osteogenic differentiation in MM, both in vitro and in vivo using a human xenograft MM model. Materials and methods Primary BM aspirates were obtained from MM patients and normal healthy donors, after obtaining informed consent in accordance with the Declaration of Helsinki. MiR-138 expression in MM-MSCs was measured by quantitative real-time PCR. Publicly available microarray data sets (GSE17306 and E-TABM-508) were analyzed for miR-138 expression in MM cells compared to normal plasma cells. To test the effect of inhibiting miR-138 function, a high-affinity 15-mer locked nucleic acid (LNA)-modified anti-miR oligonucleotide and a corresponding scramble sequence control oligonucleotide were used (In collaboration with Dr. Kauppinen, Denmark). Anti-miR-138 oligonucleotides were transfected into MM-MSCs or normal MSCs co-cultured with MM cell lines and osteogenic differentiation in MSCs was assessed by alizarin red staining. For the in vivo studies, 6-week-old female SCID-beige mice (n=6, each group) were injected intravenously with anti-miR-138 or scramble control oligonucleotides (15 mg/kg) 2 times a week. 3 weeks later, GFP+Luc+ MM.1S cells (3 × 106) were injected into mice. Anti-miR-138 or control oligonucleotides were continued until day 28 after injection of myeloma cells. At day 28, the effect of anti-miR138 was assessed by the number of osteoblastic lineage cell (OBC: Lin-/CD45-/CD31-/CD51+/Sca-1-) from hematopoietic cell-depleted, collagenase-treated crushed bones of mice by flow cytometry. Results MiR-138 expression in MSCs from MM patients (n=10) was significantly higher than MSCs from normal donors (n = 4) (P<0.05). In addition, miR-138 expression was significantly higher in MM patient tumor cells compared to normal plasma cells using two independent data sets (GSE17306 and E-TABM-508), (P<0.01 and P<0.01, respectively). In three-dimensional co-culture system of MSCs from normal donors (n=6) with MM.1S cells for 2 weeks (GSE60423), miR-138 expression was increased in 4 out of 6 donors compared to MSCs cultured alone (P<0.05). MM-MSCs (n≥3) transfected in vitro with anti-miR-138 oligonucleotides showed significantly increased osteogenic differentiation after 3-4 weeks compared to MSCs with scramble control oligonucleotides (P<0.01). Under in vitro two-dimensional co-culture conditions with MM cell lines, normal MSCs transfected with anti-miR-138 oligonucleotides showed significantly increased osteogenic differentiation compared to MSCs with scramble control oligonucleotides (P<0.001). In an in vivo human xenograft MM model, treatment of anti-miR-138 significantly increased the number of OBCs in the endosteal (Lin-/CD45-) BM stromal fraction of MM bearing SCID-beige mice at day 28 compared to scramble control oligonucleotides (P<0.05). Conclusions These findings indicate that miR-138 plays an important role in impaired osteogenic differentiation in MSCs in MM. Inhibition of miR-138 promotes osteogenic differentiation of MSCs in MM and anti-miR-138 treatment holds the potential to prevent MM induced bone loss and lytic lesions. Additional studies are ongoing to further understand the connection between MM cells and MSCs mediated by miR-138. Disclosures Roccaro: Takeda Pharmaceutical Company Limited: Honoraria. Ghobrial:Novartis: Honoraria; Noxxon: Honoraria; Celgene: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria; BMS: Honoraria, Research Funding.

Recent Patent based perspective on diagnostic and therapeutic interventions in Malignant Mesothelioma: Is Drug Repositioning knocking the door?

2021 ◽  
Vol 16 ◽  
Author(s):  
Vikas Yadav ◽  
Roghaiyeh Safari
Keyword(s):  
Malignant Mesothelioma ◽  
Drug Repositioning ◽  
Gene Signature ◽  
Therapeutic Interventions ◽  
Clinical Settings ◽  
Global Epidemic ◽  
Diagnosis And Therapy ◽  
Pubmed Database ◽  
Search Data ◽  
Novel Biomarkers

Background: Malignant Mesothelioma (MM), an orphan but aggressive malignancy of the mesothelial membrane, is a fatal tumor. Global epidemic related to malignant pleural mesothelioma is on the rise, so there is a need to explore novel biomarkers and ingenious therapeutic approaches to stalk this silent killer. Objective: The main aim of the present review is to provide a consolidated overview of the recent active patents related to diagnosis and therapy in MM that will affect its future management. Method: A search of existing literature was conducted from a PubMed database search. Recent patent information was fetched out from online accessible open-access databases. For related clinical trials, www.clinicaltrial.gov was searched. Results: Patent search data showed 72 active patents related to diagnosis and therapy in the field of MM, which we classified into eight broad categories. Of these, a maximum of 17 patents was attributed to immunotherapy, and 13 each were attributed to “Drug Repositioning” and “Biological / synthetic” based candidates. The remaining 17 patents were distributed amongst virotherapy and various miscellaneous categories. A relatively low number of patents accounts for gene signature (7), epigenetics (3), and microRNA (2) based diagnosis and therapy. Furthermore, our clinical trial-based investigation revealed the futuristic impact of listed patents in MM patient management. Conclusion: This review article has provided an overview of patent-based advancement in MM, which might become the apex in clinical settings in the future. Interestingly, immunotherapy and “drug repositioning” based therapy seems to be the front-runners in the race to provide relief.

B-Cell Markers Predict Response to Venetoclax in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2108-2108 ◽  
Author(s):  
Vikas A. Gupta ◽  
Scott Newman ◽  
Nizar J. Bahlis ◽  
Jonathan J Keats ◽  
Shannon Matulis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Research Funding ◽  
Plasma Cells ◽  
Gene Signature ◽  
Myeloma Cell ◽  
Bcl2 Family

Abstract BCL2 family members such as MCL1, BCLXL, and BCL2 are critical for cancer cell survival and therefore represent promising therapeutic targets. Both B cells and CLL cells depend primarily on BCL-2 and are thus sensitive to the BCL2 specific inhibitor venetoclax, while plasma cells and multiple myeloma typically depend on Mcl-1 and would therefore be resistant to venetoclax. However, a subset of myeloma is venetoclax sensitive based on recent in vitro and clinical trial data. In preliminary results from a phase I trial of venetoclax in multiple myeloma, 40% of patients positive for t(11;14) had objective responses, while only 6% of t(11;14) negative patients responded. We have made similar observations with in vitro testing of 30 freshly isolated myeloma patient samples, identifying both non-t(11;14) samples sensitive to venetoclax as well as resistant t(11;14) positive samples. Together, these results suggest not only that a subset of multiple myeloma is co-dependent on BCL2 but also that t(11;14) is neither necessary nor sufficient for responding to venetoclax. We therefore set out to identify other factors that may predict BCL2 dependence in multiple myeloma. Previous studies of t(11;14) myeloma have noted increased expression of CD20, CD23, CD79a, and PAX5 which are typically associated with B cells prior to their differentiation into plasma cells. Based on these observations we hypothesized that venetoclax sensitivity in myeloma may be associated with the retention of B cell properties including BCL2 dependence. We probed an online expression database of myeloma cell lines for non-t(11;14) cell lines expressing CD20 and identified two cell lines, OCI-My5 and PCM6, both of which we found to have an IC50 of approximately 50nM when treated with venetoclax. We went on to characterize a panel of 13 cell lines. In addition to OCI-My5 and PCM6, 4 other cell lines were sensitive to venetoclax, all positive for t(11;14). Of the 7 venetoclax resistant cell lines, 2 were t(11;14) positive. Protein levels of MCL1, BCLXL, and BCL2 were comparable among the 13 lines and therefore anti-apoptotic expression is unlikely to be responsible for venetoclax sensitivity. Consistent with our previous co-immunoprecipitation studies, more of the pro-apoptotic BIM was bound to BCL2 in venetoclax sensitive lines compared to resistant lines. In the absence of differences in BCL2 family expression, we next sought to identify other B cell related features correlating with venetoclax sensitivity. We used RNAseq data from our 13 cell lines to compare the expression of 100 genes previously reported to be differentially expressed between normal B cells and plasma cells. Interestingly, unsupervised clustering revealed a group of venetoclax sensitive cells enriched for other B cell associated genes. GSEA revealed enrichment of genes associated with immune system activation at a p < 0.001. We also analyzed the differential expression of genes between our sensitive and resistant lines and again identified overexpression of B cell related genes such as CD20, CD79A, STAT5A, and RASGRP2 in venetoclax sensitive lines, though no single marker was present in all of the venetoclax sensitive lines. We examined the expression of CD20, CD79a, and CD79b in the CoMMpass data set (IA8) as well and found that they were not co-expressed in most patients, again suggesting that no single marker is likely to be predictive. Finally, we created a gene signature from the top differentially expressed genes to predict sensitivity or resistance to venetoclax and used this signature to evaluate a database of 68 myeloma cell lines. One of the top hits predicted to be sensitive by our gene signature is the t(11;14) negative line MOLP2, and indeed this cell line was recently reported to be highly responsive to venetoclax. In conclusion, B cell markers and our gene signature correlate with BCL2 dependence and venetoclax sensitivity independent of t(11;14). Disclosures Bahlis: BMS: Honoraria; Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria. Nooka:Spectrum, Novartis, Onyx pharmaceuticals: Consultancy. Kaufman:Pharmacyclics: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Lonial:Onyx: Consultancy; Onyx: Consultancy; BMS: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Millenium: Consultancy; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy.

Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines

2019 ◽  
Vol 19 (2) ◽  
pp. 112-119 ◽  
Author(s):  
Mariana B. de Oliveira ◽  
Luiz F.G. Sanson ◽  
Angela I.P. Eugenio ◽  
Rebecca S.S. Barbosa-Dantas ◽  
Gisele W.B. Colleoni
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Viability ◽  
Cell Lines ◽  
Treatment Options ◽  
Compensatory Mechanism ◽  
Protein Homeostasis ◽  
Protein Response ◽  
Rpmi 8226

Introduction:Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).Methods:We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.Results:For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.Conclusion:Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

Recent Patents on Anti-Cancer Potential of Helenalin

2020 ◽  
Vol 15 (2) ◽  
pp. 132-142
Author(s):  
Priyanka Kriplani ◽  
Kumar Guarve
Keyword(s):  
Synergistic Effects ◽  
Therapeutic Interventions ◽  
Active Constituent ◽  
Scientific Impact ◽  
Isolation Techniques ◽  
Anti Cancer ◽  
Prevention Of Cancer ◽  
Synthetic Derivatives

Background: Arnica montana, containing helenalin as its principal active constituent, is the most widely used plant to treat various ailments. Recent studies indicate that Arnica and helenalin provide significant health benefits, including anti-inflammatory, neuroprotective, antioxidant, cholesterol-lowering, immunomodulatory, and most important, anti-cancer properties. Objective: The objective of the present study is to overview the recent patents of Arnica and its principal constituent helenalin, including new methods of isolation, and their use in the prevention of cancer and other ailments. Methods: Current prose and patents emphasizing the anti-cancer potential of helenalin and Arnica, incorporated as anti-inflammary agents in anti-cancer preparations, have been identified and reviewed with particular emphasis on their scientific impact and novelty. Results: Helenalin has shown its anti-cancer potential to treat multiple types of tumors, both in vitro and in vivo. It has also portrayed synergistic effects when given in combination with other anti- cancer drugs or natural compounds. New purification/isolation techniques are also developing with novel helenalin formulations and its synthetic derivatives have been developed to increase its solubility and bioavailability. Conclusion: The promising anti-cancer potential of helenalin in various preclinical studies may open new avenues for therapeutic interventions in different tumors. Thus clinical trials validating its tumor suppressing and chemopreventive activities, particularly in conjunction with standard therapies, are immediately required.

scholarly journals Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

2021 ◽  
Author(s):  
Yu-bo Zhou ◽  
Yang-ming Zhang ◽  
Hong-hui Huang ◽  
Li-jing Shen ◽  
Xiao-feng Han ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Targets ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Preclinical Study ◽  
Parp Cleavage ◽  
Rpmi 8226 ◽  
Ongoing Phase

AbstractHDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

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