scholarly journals Chidamide, a Novel Histone Deacetylase Inhibitor, Inhibits Multiple Myeloma Cells Proliferation through Succinate Dehydrogenase Subunit a

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1965-1965
Author(s):  
Yifeng Sun ◽  
Peng Liu ◽  
Jing Li
Keyword(s):  
Multiple Myeloma ◽  
Synergistic Effect ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Target Gene ◽  
Chemotherapeutic Agents ◽  
Lower Percentage ◽  
Ros Production ◽  
Rt Pcr ◽  
Deacetylase Inhibitor

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.

A Phase I Study of Oral Melphalan Combined with LBH589 for Patients with Relapsed or Refractory Multiple Myeloma (MM).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1855-1855 ◽  
Author(s):  
James R. Berenson ◽  
Ori Yellin ◽  
Ralph V. Boccia ◽  
Youram Nassir ◽  
Shellie Rothstein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Phase I ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Chemotherapeutic Agents ◽  
Treatment Schedule ◽  
Deacetylase Inhibitor ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 1855 Poster Board I-881 We and others have shown that LBH589, a potent histone deacetylase inhibitor (HDACi), significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity triggered by chemotherapeutic agents. Using our SCID-hu models of MM, we have also shown a striking inhibition of MM cell growth in vivo when LBH589 was combined with low doses of melphalan compared to treatment with either drug alone. Thus, these preclinical studies provided the rationale for evaluating the combination of oral melphalan with oral LBH589 for the treatment of MM patients with relapsed or refractory disease. We present the results of an ongoing phase I, open-label, multicenter, dose-escalation study. The initial treatment schedule involved administering patients oral LBH589 every Monday, Wednesday and Friday (MWF) combined with oral melphalan on days 1–5 of a 28-day cycle. Patients were to be treated to maximum response plus 2 additional cycles or complete 8 cycles of therapy without disease progression. To date, 15 patients have been enrolled. At study entry, eleven patients (73%) had International Staging System II or III MM. Fourteen patients were previously treated with melphalan. Three subjects were enrolled into the first cohort (oral LBH589 10 mg; melphalan 0.05 mg/kg) and all experienced significant hematological adverse events. During cycle 1, 2 of 3 subjects had grade 3 thrombocytopenia and all 3 patients developed grade 3 neutropenia. As a result, the melphalan dosing schedule was changed from being administered on days 1-5 to only on days 1, 3 and 5. Three subjects were enrolled into this modified first cohort using the same doses of both drugs. One subject in this cohort experienced both a grade 3 neutropenia and thrombocytopenia. However, there were no DLTs in this cohort and so enrollment into the next cohort (LBH589 at 20 mg and melphalan at 0.05 mg/kg) was initiated. In this cohort, one subject experienced a DLT (grade 4 thrombocytopenia) while the other two developed grade 3 thrombocytopenia. One patient achieved a immunofixation (IF)+ CR but withdrew consent due to intolerable fatigue. As a result, three additional patients were evaluated at this dose level, and two patients have responded including one active patient who is now in PR and another one also achieved a PR but had to be taken off study due to persistent grade 3 neutropenia. Based on the ongoing significant fatigue among patients treated with LBH89 throughout the treatment cycle, the protocol was revised so that the HDACi was administered only during the first two weeks (days 1, 3, 5, 8, 10, and 12) of the 28-day schedule. To date, 3 patients have recently started treatment with this modified schedule of LBH589 at 20 mg and melphalan at 0.05 mg/kg again administered on days 1, 3 and 5 of each 28-day cycle but are not yet evaluable for response. Thus, 12 patients are currently evaluable for response and 4 (33 %) who had previously received melphalan at higher doses have achieved a response including 1 complete response (IF+ CR) and 3 partial responses. Another 4 patients showed stable disease so that disease control was achieved overall in 8 (67%) patients. Overall, the most common ≥ grade 3 adverse events included reversible neutropenia and thrombocytopenia. Specifically, there were 6 cases of grade 3 neutropenia, 6 with grade 3 thrombocytopenia and 1 with grade 4 thrombocytopenia. All of these cytopenias were reversible. Because of the encouraging response rate (33%) that has already been observed in this relapsed and refractory population of heavily pretreated MM patients previously treated with melphalan, an expanded Phase II trial will be conducted using this combination once the MTD has been determined and schedule of dosing has been optimized. Disclosures: Berenson: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding, Speakers Bureau. Off Label Use: LBH589 is a histone deacetylase inhibitor that is used for the treament of multiple myeloma. Rothstein:Novartis Pharmaceuticals Corporation: Employment.

The Proteasome Inhibitor Bortezomib and Histone Deacetylase Inhibitor SAHA Sinergistically Inhibit Proliferation and Induce Apoptosis of Megakaryoblastic MO7-e Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4389-4389
Author(s):  
Sara Galimberti ◽  
Martina Canestraro ◽  
Simone Pacini ◽  
Rita Fazzi ◽  
Enrico Orciuolo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Line ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Proteasome Inhibitor ◽  
Myeloproliferative Disorders ◽  
Ros Production ◽  
Deacetylase Inhibitor ◽  
Apoptotic Effect

Abstract PS-341 (Bortezomib) is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo antitumor activity that induces apoptosis in different human cancer cell lines. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been reported to induce apoptosis of leukemic cells by increasing the cyclin-dependent kinase inhibitor p21 or generating reactive oxygen species (ROS). Co-exposure of BCR/ABL-positive cells both sensitive and resistant to imatinib to these compounds has been previously reported resulting in an increased apoptotic rate. To extend this observation, we examined the effect of treatment with bortezomib or/and SAHA of a megakaryoblastic cell line (MO7-e). Cell proliferation, ROS production, cell cycle progression, induction of apoptosis and differentiation has been investigated. Bortezomib was shown to retain NF-kB in the cytoplasm and inhibit cell growth (IC50=20nM), in a dose/time-dependent way. This anti-proliferative activity resulted to be lineage-specific, because other leukemic cell lines were unaffected by the bortezomib treatment. Moreover, bortezomib in MO7-e cells increased ROS production and induced a significant pro-apoptotic effect (50% vs 5% in control). Finally, cell cycle was blocked in the G2 phase and bortezomib was able to down-regulate WT1 expression, gene that could play a relevant prognostic role in myeloproliferative disorders. Moreover, any significant effect on cell differentiation was found. SAHA also resulted able to inactivate NF-kB and to inhibit cell proliferation, at 1.5 uM. It did not increase significantly ROS production, blocked cell cycle in the G1 phase and down-regulated WT1 expression (10 fold minus than bortezomib). Neverthelles, SAHA also did not induce differentiation of megakaryoblatic cells. Co-exposure of this cell line to minimally toxic concentrations of bortezomib (5 nM) and SAHA (0.5 uM), resulted in a significant increase of anti-proliferative (50% of growth inhibition vs 15% with bortezomib and 10% with SAHA alone) and pro-apoptotic effect (45% vs 20% of bortezomib and 15% of SAHA alone). Interestingly, immunocitochemistry assays detecting the NF-kB p65 subunit showed that the co-exposure to bortezomib and SAHA resulted in a minor NF-kB inactivation than that achieved with single compounds. This finding was confirmed by the pre-incubation of MO7-e cells with SAHA in respect of the pre-incubation with bortezomib or the simultaneously addition of the two drugs. In fact, pre-incubating megakaryoblasts with SAHA, the anti-proliferative effect of bortezomib significantly decreased. In conclusion, this study supports the association of a proteasome with a histone deacetylase inhibitor, in a time-sequence-related way, especially in chronic myeloproliferative disorders where a spontaneous NF-kB activation and a WT1 over-expression have been reported.

scholarly journals Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma

Cancer ◽  
2010 ◽  
Vol 117 (2) ◽  
pp. 336-342 ◽  
Author(s):  
Ruben Niesvizky ◽  
Scott Ely ◽  
Tomer Mark ◽  
Sangeeta Aggarwal ◽  
Janice L Gabrilove ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Phase 2 ◽  
Refractory Multiple Myeloma ◽  
Phase 2 Trial ◽  
Deacetylase Inhibitor

OSU-HDAC42, a Novel Histone Deacetylase Inhibitor, Induces Apoptosis in a Caspase-Dependent Manner and Induces p21WAF1/CIP1 and p16 Expression in Multiple Myeloma Cell Lines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5078-5078
Author(s):  
Valerie L. White ◽  
Shuhong Zhang ◽  
David Lucas ◽  
Ching-Shih Chen ◽  
Sherif S. Farag
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Myeloma Cell ◽  
Dependent Manner ◽  
In Vitro Activity ◽  
Myeloma Cells ◽  
Deacetylase Inhibitor

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.

Sign in / Sign up

Export Citation Format

Share Document