Gene signatures to therapeutics: Assessing the potential of ivermectin against t(4;14) multiple myeloma

Abstract

BACKGROUND

Multiple myeloma (MM) is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow. The translocation, (t)(4;14), results in high-risk MM with limited treatment alternatives. Thus, there is an urgent need for identification and validation of potential treatments for this MM subtype. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets.

AIM

To elucidate the molecular basis and search for potential effective drugs of t(4;14) MM subtype by employing a comprehensive approach.

METHODS

The transcriptional signature of t(4;14) MM was sourced from the Gene Expression Omnibus. Two datasets, GSE16558 and GSE116294, which included 17 and 15 t(4;14) MM bone marrow samples, and five and four normal bone marrow samples, respectively. After the differentially expressed genes were identified, the Cytohubba tool was used to screen for hub genes. Then, the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Using the STRING database and Cytoscape, protein–protein interaction networks and core targets were identified. Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis, respectively.

RESULTS

In this study, a total of 258 differentially expressed genes with enriched functions in cancer pathways, namely cytokine receptor interactions, nuclear factor (NF)-κB signaling pathway, lipid metabolism, atherosclerosis, and Hippo signaling pathway, were identified. Ten hub genes (cd45, vcam1, ccl3, cd56, app, cd48, btk, ccr2, cybb, and cxcl12) were identified. Nine drugs, including ivermectin, deforolimus, and isoliquiritigenin, were predicted by the Connectivity Map database to have potential therapeutic effects on t (4;14) MM. In molecular docking, ivermectin showed strong binding affinity to all 10 identified targets, especially cd45 and cybb. Ivermectin inhibited t(4;14) MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro. Furthermore, ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14) MM cells.

CONCLUSION

Collectively, the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14) MM diagnosis and treatment, with ivermectin emerging as a potential therapeutic alternative.

Keywords: Multiple myeloma, Functional enrichment analysis, Molecular docking simulation, Gene expression profiling, Therapeutic target, Ivermectin

Core Tip: Multiple myeloma is a hematological malignancy with a significant impact on public health, and the t(4;14) subtype is particularly aggressive and resistant to existing treatments. Our study addresses the urgent need for new therapeutic approaches by employing a comprehensive approach that includes bioinformatics analysis, molecular docking, and experimental validation. We identified ten key genes associated with t(4;14) multiple myeloma (MM), shedding light on the molecular basis of this subtype. We explored the potential of ivermectin to assess whether it may be “repurposed” as a therapeutic agent for t(4;14) MM. Our findings indicate that ivermectin not only inhibits MM cell growth but also induces apoptosis via the nuclear factor-κB signaling pathway.