scholarly journals Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy

2021 ◽  
Vol 12 (20) ◽  
pp. 6198-6208
Author(s):  
Yanjuan He ◽  
Duanfeng Jiang ◽  
Kaixuan Zhang ◽  
Yinghong Zhu ◽  
Jingyu Zhang ◽  
...  
Cancer ◽  
2010 ◽  
Vol 117 (2) ◽  
pp. 336-342 ◽  
Author(s):  
Ruben Niesvizky ◽  
Scott Ely ◽  
Tomer Mark ◽  
Sangeeta Aggarwal ◽  
Janice L Gabrilove ◽  
...  

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1965-1965
Author(s):  
Yifeng Sun ◽  
Peng Liu ◽  
Jing Li

Abstract Most patients with multiple myeloma (MM) would finally relapse. Current chemotherapy regimens have limited effect on relapse MM patients. As a new histone deacetylase inhibitor, chidamide has been used in malignancy treatment such as peripheral T-cell lymphoma. However, it is still unknown if chidamide can be used in MM. To determine the target gene of chidamide in MM patients, we performed RNA-Seq analysis using 3 MM patients' bone marrow mononuclear cells. Their BMMCs were cultured with 6μM chidamide or not, and six of the most significantly changed coding genes were selected. Realtime RT-PCR showed that compared with DMSO-treated cells, after adding 6μM chidamide, the expression of SDHA and FCER2 was increased and MRPL30 decreased. The expression of SDHA was upregulated and ITGA7 was downregulated in MM patients. Based on the data above, SDHA was considered as the most valuable target gene of chidamide in MM. Realtime RT PCR also showed that SDHA expression in normal volunteers was the highest and followed by patients with MGUS and initial MM. Patients with relapse MM had the lowest SDHA expression. To assess the effects of chidamide on MM cells, we next performed cell proliferation and invasion assay. Chidamide dramatically inhibited proliferation of myeloma cell lines (H929 and OPM-2). However, when SDHA was knocked down by siRNA, this inhibition effect was not dramatically as before in H929 cells. Similarly, chidamide-treated H929 cells achieved a notably lower percentage of cell invasion than those treated with DMSO. Thus, when SDHA was knocked down, this invasive ability was not significantly changed whether chidamide was added or not. CCK8 assay was used to determine dose-response curves of chemotherapeutic agents and synergistic effect of chidamide combined with other agents. he combination index (CI) of lenalidomide and low concentration of bortezomib yielded many of the data points to the area <1 when combined with chidamide treatment, denoting synergistic interactions in MM cell line. Interestingly, when SDHA was knocked down, cells apoptosis induced by bortezomib and lenalidomide combined with chidamide greatly decreased, especially by lenalidomide, which indicated the synergistic effect between chidamide and other agents was induced by SDHA. When SDHA was knocked down by siRNA, most of CI between chidamide and bortezomib or lenalidomide also raised above 1, which indicated the synergistic effect tended to disappear. In order to gain further mechanism of chidamide-SDHA-MM axis, Western Blot was used. As a result, it showed that when SDHA was knocked down in H929 cells by siRNA, expression of HIFα protein was increased. HIFα decreased after adding 6μM chidamide. However, when SDHA was knocked down, chidamide did not regulate the expression of HIFα any longer. ROS in MM patients were much higher than that in normal people, which caused by higher HIFα expression in large extent. Chidamide inhibited ROS production, and similar to HIFα, the ROS production was not sensitive to chidamide any more when SDHA was knocked down. Our findings clatify the mechanism of chidamide treatment in MM through SDHA and reveal a novel therapeutic strategy of MM treatment. Figure. Figure. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5078-5078
Author(s):  
Valerie L. White ◽  
Shuhong Zhang ◽  
David Lucas ◽  
Ching-Shih Chen ◽  
Sherif S. Farag

Abstract Multiple myeloma (MM) is a neoplastic disorder characterized by accumulation of slowly-proliferating clonal plasma cells. OSU-HDAC42 [a.k.a. (S)-HDAC-42] is a novel histone deacetylase inhibitor that induces apoptosis in various types of cancer cells and is being developed as an anti-cancer therapy in the NCI Rapid Access to Intervention Therapy (RAID) program. In this study, we tested the in vitro activity of OSU-HDAC42 against human MM cells. OSU-HDAC42 induced myeloma cell death, with an LC50 of less than 1.6μM after 48 hours in the four cell lines tested - U266, IM-9, RPMI 8226 and ARH-77 using the MTT assay. OSU-HDAC42 induced cleavage of caspases 3, 8 and 9, as well as polyADP-ribose polymerase (PARP). Addition of the pan-caspase inhibitor Q-VD-OPH before exposure to the drug prevented apoptosis at 48 hours, as determined by Annexin V/propidium iodide staining. These results indicate that OSU-HDAC42 induced apoptosis by a mainly caspase-dependent manner. Bax expression was up-regulated at 24 and 48 hours, while Bcl-2 remains relatively constant. Mcl-1 showed increasing cleavage at increasing doses of OSU-HDAC42. These findings support a mitochondrial pathway of apoptosis. Cell cycle suppressor proteins p21WAF1/CIP1 and p16 were also significantly induced after treatment with the drug, suggesting that OSU-HDAC42 may also acts on pathways to halt cell cycle progression. In addition, the gp130 (signal-transducing) subunit of the IL-6 receptor was down-regulated by OSU-HDAC42 exposure. The tyrosine-phosphorylated form of STAT3, which is phosphorylated by dimerized gp130, was also dramatically reduced following incubation with OSU-HDAC42, supporting the finding that gp130 expression is diminished. As IL-6 is an important growth and survival factor for MM cells, down-regulation of gp130 may be an important mechanism for the activity of OSU-HDAC42 against MM cells. TRAIL, FasL, XIAP, and p53 expression were not affected by OSU-HDAC42. While other HDAC inhibitors have been shown to activate the death receptor pathway or down-regulate XIAP, this was not observed with OSU-HDAC42 in myeloma cells. In conclusion, OSU-HDAC42 has in vitro activity against myeloma cells and acts via activation of caspases, inducing the cell cycle suppressors p21WAF1/CIP1 and p16, as well as interfering with the IL-6 signal transduction pathway.


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