A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma

Galli, Mónica; Salmoiraghi, Silvia; Golay, Joseé; Gozzini, Antonella; Crippa, Claudia; Pescosta, Norbert; Rambaldi, Alessandro

doi:10.1007/s00277-009-0793-8

Cited by 97 publications

(56 citation statements)

References 20 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several types of HDACI have been used to treat patients with MM in clinical trials, including vorinostat (SAHA) and panobinostat, however, the response is poor (11)(12)(13). The modest, yet encouraging, single-agent activity observed with HDAC inhibitors in heavily pretreated patients with MM has led to their evaluation in combination with other novel therapeutic agents (14)(15)(16)(17)(18). The clinical activity of HDAC inhibitors in combination with proteasome inhibitors, IMiDs and conventional cytotoxic agents has been demonstrated in heavily pretreated MM patients, supporting the continued evaluation of these regimens in this patient population (19).…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

Wang

Zhang

2012

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. The aim of the present study was to investigate the synergistic effects of valproic acid (VPA) and arsenic trioxide (ATO) on the proliferation of RPMI8226 cells and the possible underlying mechanisms. Cell apoptosis was assessed by flow cytometry. The mRNA expression levels were analyzed by semi-quantitative polymerase chain reaction, and the protein expression levels were analyzed by western blotting. The histone acetylation and methylation states of the gene promoters were detected using a chromatin immunoprecipitation technique. The apoptotic rates of the RPMI8226 cells in the combined drug groups were significantly increased compared with those of the single drug groups (P<0.05). The mRNA and protein expression levels of Bcl-2 and the expression levels of HDAC1 mRNA and H3K9me2 protein decreased significantly in the combined groups compared with the single drug groups. The mRNA and protein expression levels of Bax, Caspase 8, Caspase 9 and LSD1, and the protein expression of acetylated H3 increased significantly in the combination groups compared with the single drug groups. Histone methylation and acetylation of the Bcl-2 and bax gene promoters were increased in the combination groups compared with the single drug groups. VPA and ATO had synergistic effects on the proliferation of RPMI8226 cells, which may have been associated with the decreased expression of Bcl-2 and the increased expression levels of Bcl-2-associated X protein, Caspase 8 and Caspase 9. Therefore, the expression levels of the Bcl-2 gene family may have been regulated by the levels of gene promoter methylation and acetylation. IntroductionMultiple myeloma (MM) is a plasma cell disorder, characterized by anemia, renal disease, lytic bone disease, and immune dysfunction. MM is one of the most common types of hematological malignancy in China (1). Although currently approved treatments for newly diagnosed MM, including high-dose chemotherapy followed by autologous transplantation, and novel drugs, including proteasome inhibitors and immunomodulatory agents (IMiDs), have led to increased survival rates, the majority of patients will eventually relapse and become refractory to treatment (2). Therefore, patients with relapsed or refractory MM have an unmet requirement for safe and efficacious novel therapies.Arsenic trioxide (ATO) has been suggested as an option for the treatment of relapsing or refractory MM. In vitro, ATO has been found to induced myeloma cell apoptosis, and monotherapy with ATO results in partial response rates between 0 and 17%, and minimal responses between 7 and 33%, resulting in mean overall response rates of 30% for treatment of myeloma (3-5).In order to improve the treatment response rates in patients with MM, ATO has been combined with other novel drugs, including proteasome inhibitors, IMiDs and dexamethsone, for the treatment of MM. The overall response rates in these combined regimens vary widely between 12 and 100% (6-8). It is necessary to identify novel combinations of ATO with other drugs, to offer nov...

show abstract

Section: Discussionmentioning

confidence: 99%

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

Wang

Zhang

2012

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…This suggests that drugs that reset the chromatin assembly may correct the pathological epigenetic programming associated with stress-related disorders, such as depression and anxiety. In particular, HDAC inhibitors are currently marketed for the treatment of cancer, including drug-resistant forms of leukemia and lymphomas, but long-term use of these drugs may be seriously limited by a number of adverse effects, including nausea, fatigue, transient thrombocytopenia, and, in some instances, myelosuppression (7,8). In contrast, drugs that directly promote processes of acetylation represent a potential alternative to the use of HDAC inhibitors in human disorders.…”

mentioning

confidence: 99%

L -acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

Nasca

Xenos

Barone

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

237

217

View full text Add to dashboard Cite

Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.BDNF | histone acetylation | MDD | glutamatergic neurotransmission | chromatin

show abstract

“…Protein tyrosine kinases can catalyze the transfer of the γ-phosphoryl group on the ATP molecule to the tyrosine residues of substrate proteins, making them phosphorylated (16). The protein tyrosine kinase family with over 90 members is divided into two subfamilies, the receptor tyrosine kinases (RTKs) and the nonreceptor tyrosine kinases (nRTKs) (Figure 1) (21,22).…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors merged with protein tyrosine kinase inhibitors

Zhou

Zhang

2015

DD&T

View full text Add to dashboard Cite

A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma

Cited by 97 publications

References 20 publications

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

L -acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

Histone deacetylase inhibitors merged with protein tyrosine kinase inhibitors

Contact Info

Product

Resources

About