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Introduction Evodiamine (Evo) is one of the main bioactive components derived from the drying mature fruit of the genus Evodia rutaecarpa (Juss.) Benth. Although Evo has shown its anti-cancer activity in several cancers, the effects on multiple myeloma (MM) remain unknown. In this study, we aim to investigate the cytotoxic role of Evo on MM cells. Methods CCK-8 assay, apoptotic cell analysis, xenografted mice model, caspase activity assay and mitochondrial membrane potential assay were performed. Results We found that Evo selectively inhibits cell proliferation and increases apoptosis rate in MM cells, but not in healthy B lymphocytes, in a time and dose-dependent manner. Evo treatment significantly activated caspase-3 and -9 in MM cells. Evo also increased cytochrome C expression and ROS production in cytosol in a dose-dependent manner, which was abolished by MitoTEMPO cotreatment. In addition, co-treatment with bortezomib and Evo showed a more potent reduction of cell viability and a higher apoptosis than that of bortezomib single treatment in U266 and RPMI8226 cells. Conclusion We provided evidence to demonstrate that Evo selectively suppresses cell growth and increases apoptosis rate in MM cells through the intrinsic apoptosis pathway. Application of Evo and bortezomib might enhance the anti-cancer effect on MM cells.

Clinical outcomes of patients with multiple myeloma (MM) have almost doubled the overall survival over the last decade owing to the use of proteasome inhibitor such as bortezomib (BTZ). However, some patients with MM develop primary resistance to BTZ, whereas others develop resistance after treatment. In this study, we investigated relationships between BTZ resistance and dysfunction of long non-coding RNAs (lncRNAs) in patients with MM. Bone marrow samples were collected from patients with MM and healthy donors for lncRNA microarray and survival analyses. To investigate functions and underlying mechanisms of lncRNA-mediated BTZ resistance in MM, we performed CCK-8 assays, flow cytometry analyses, dual luciferase report gene assays, and RNA pulldown assays with samples from nude mice carrying tumor xenografts and in clinical samples. Differentially expressed lncRNA myocardial infarction associated transcripts (MIAT) were highly expressed in patients with MM compared with healthy controls, and were predictive of poor survival outcomes. Moreover, MIAT expression was significantly increased in BTZ-resistant patients with MM compared with newly diagnosed patients with MM, and was identified as a BTZ-inducible lncRNA. Specifically, BTZ upregulated MIAT expression through increased stat1 phosphorylation. Silencing of MIAT inhibited MM cell growth and sensitized MM cells to BTZ by negatively regulating miR-29b. Our data demonstrated the utility of MIAT as a tool for overcoming BTZ resistance in patients with MM.

Purpose: Circular RNA (circRNA) is a key regulatory factor in the development and progression of human tumors. However, the working mechanism and clinical significance of most circRNAs remain unknown in human cancers, including multiple myeloma (MM). Patients and Methods: This study employs high-throughput circRNA microarray with bioinformatics to identify differentially expressed circRNAs in patients with MM. The hsa_circ_0007841 expressions were observed in the MM tissues of 86 patients. Drug-resistant cell lines and pathological features were also detected. In addition, the relationship between hsa_circ_0007841 expressions in the MM tissues and the pathological features of patients with MM were evaluated and role of hsa_circ_0007841 as a potential biomarker and therapeutic target was assessed. Results: The results show that in the MM cell lines and drug-resistant cell lines, hsa_circ_0007841 expression was significantly upregulated, which was closely associated with disease prognosis. Specifically, hsa_circ_0007841 upregulation was correlated with chromosomal aberrations such as gain 1q21, t (4:14) and mutations in ATR and IRF4 genes. This finding was corroborated in large samples. Finally, bioinformatics analysis showed that eight differentially expressed miRNAs and 10 candidate mRNAs interacted with hsa_circ_0007841, shedding some new light on the basic functional research. Conclusion: This study may be the first to report that hsa_circ_0007841 is significantly upregulated in MM. It also suggests that hsa_circ_0007841 may be a novel biomarker for MM and its involvement in the progression of MM.

Aim: To investigate the prognostic value of lncRNA NR_046683 in multiple myeloma (MM). Methods: High-throughput lncRNA array was combined with bioinformatics techniques to screen differentially expressed lncRNA in MM. qRT-PCR was adopted to determine the expression of target lncRNAs in MM patients and controls. Results: It was found for the first time that lncRNA NR_046683 is closely related to the prognosis of MM. It was also detected in tumor cell lines KM3, U266, especially in drug-resistant cell lines KM3/BTZ and MM1R. The NR_046683 expression differed significantly in patients of different MM subtypes and staging. Moreover, the overexpression of NR-046683 is closely related to β2-microglobulin. We also found that the overexpression of NR-046683 correlates to chromosomal aberrations, such as del(13q14), gain 1q21, and t(4;14). Conclusion: lncRNA NR_046683 can serve as a novel biomarker for potential drug target and prognostic prediction in MM.