Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

Imai, Yumiko; Ohta, Emi; Takeda, Satoshi; Sunamura, Satoko; Ishibashi, Mariko; Tamura, Hideto; Wang, Yanhua; Deguchi, Atsuko; Tanaka, Junji; Maru, Yoshiro; Motoji, Toshiko

doi:10.1172/jci.insight.85061

Cited by 29 publications

(61 citation statements)

References 67 publications

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“…This includes a study that addressed defective B cell activation stemming from calcineurin inactivation . We found that PPP3CA was highly expressed in CD138‐positive bone marrow cells from patients with advanced MM . These results indicate a possible correlation between high PPP3CA expression and the pathogenesis of MM.…”

Section: Histone Deacetylase Inhibitors Induce Calcineurin Degradatiomentioning

confidence: 78%

“…Combined panobinostat with bortezomib and dexamethasone therapy is expected to be effective even in patients who are resistant to bortezomib . The analyses of our patients revealed that PPP3CA expression was significantly higher in patients who were bortezomib‐resistant than in those who were sensitive . Bortezomib reduced PPP3CA expression through HDAC6 inhibition and direct transcriptional suppression of PPP3CA .…”

Section: Clinical Significance Of Targeting Ppp3ca In MM Treatmentmentioning

confidence: 88%

“…We discovered that panobinostat induces degradation of PPP3CA, a catalytic subunit of calcineurin, in MM cells (Fig. ) . Protein phosphatase 3 catalytic subunit α is a serine/threonine protein phosphatase, and NFATc1 is one of its dephosphorylation targets .…”

Section: Histone Deacetylase Inhibitors Induce Calcineurin Degradatiomentioning

confidence: 98%

“…However, HSP90 inhibitors such as 17‐AAG induce protein expression of HSP70, which protects cancer cells from apoptosis and may reduce the antimyeloma effects of this combination therapy . However, increases in HSP70 expression by panobinostat alone or in combination with FK506 proved that the loss of the antimyeloma effects due to HSP70 expression were less pronounced with this combination therapy than they were with direct inhibition of HSP90 …”

Section: Clinical Significance Of Targeting Ppp3ca In MM Treatmentmentioning

confidence: 99%

“…Treatment with ACY‐1215, a selective HDAC6 inhibitor, resulted in PPP3CA degradation through its release from HSP90 . Therefore, panobinostat may induce protein degradation of PPP3CA by blocking the chaperone function of HSP90 . PPP3CA has been shown to be indispensable to the maintenance of MM cell growth via NF‐κB signaling.…”

Section: Histone Deacetylase Inhibitors Induce Calcineurin Degradatiomentioning

confidence: 99%

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Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies

2016

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Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities of HDACs, especially involving non‐histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors show some efficacy in the treatment of acute myelogenous leukemia with AML1‐ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T‐cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan‐HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression‐free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib.

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Section: Histone Deacetylase Inhibitors Induce Calcineurin Degradatiomentioning

confidence: 78%

Section: Clinical Significance Of Targeting Ppp3ca In MM Treatmentmentioning

confidence: 88%

Section: Histone Deacetylase Inhibitors Induce Calcineurin Degradatiomentioning

confidence: 98%

Section: Clinical Significance Of Targeting Ppp3ca In MM Treatmentmentioning

confidence: 99%

Section: Histone Deacetylase Inhibitors Induce Calcineurin Degradatiomentioning

confidence: 99%

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Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies

2016

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Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma

McGuire

Nerlakanti

et al. 2020

Intl Journal of Cancer

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Overall survival rates for patients with advanced osteosarcoma have remained static for over three decades. An in vitro analysis of osteosarcoma cell lines for sensitivity to an array of approved cancer therapies revealed that panobinostat, a broad spectrum histone deacetalyase (HDAC) inhibitor, is highly effective at triggering osteosarcoma cell death. Using in vivo models of orthotopic and metastatic osteosarcoma, here we report that panobinostat impairs the growth of primary osteosarcoma in bone and spontaneous metastasis to the lung, the most common site of metastasis for this disease. Further, pretreatment of mice with panobinostat prior to tail vein inoculation of osteosarcoma prevents the seeding and growth of lung metastases. Additionally, panobinostat impaired the growth of established lung metastases and improved overall survival, and these effects were also manifest in the lung metastatic SAOS2-LM7 model. Mechanistically, the efficacy of panobinostat was linked to high expression of HDAC1 and HDAC2 in osteosarcoma, and silencing of HDAC1 and 2 greatly reduced osteosarcoma growth in vitro. In accordance with these findings, treatment with the HDAC1/2 selective inhibitor romidepsin compromised the growth of osteosarcoma in vitro and in vivo. Analysis of patient-derived xenograft osteosarcoma cell lines further demonstrated the sensitivity of the disease to panobinostat or romidepsin. Collectively, these studies provide rationale for clinical trials in osteosarcoma patients using the approved therapies panobinostat or romidepsin.

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Histone deacetylase‐based dual targeted inhibition in multiple myeloma

Ferro

Pantazaka

Athanassopoulos

et al. 2023

Medicinal Research Reviews

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Despite enormous advances in terms of therapeutic strategies, multiple myeloma (MM) still remains an incurable disease with MM patients often becoming resistant to standard treatments. To date, multiple combined and targeted therapies have proven to be more beneficial compared to monotherapy approaches, leading to a decrease in drug resistance and an improvement in median overall survival in patients. Moreover, recent breakthroughs highlighted the relevant role of histone deacetylases (HDACs) in cancer treatment, including MM. Thus, the simultaneous use of HDAC inhibitors with other conventional regimens, such as proteasome inhibitors, is of interest in the field. In this review, we provide a general overview of HDAC‐based combination treatments in MM, through a critical presentation of publications from the past few decades related to in vitro and in vivo studies, as well as clinical trials. Furthermore, we discuss the recent introduction of dual‐inhibitor entities that could have the same beneficial effects as drug combinations with the advantage of having two or more pharmacophores in one molecular structure. These findings could represent a starting‐point for both reducing therapeutic doses and lowering the risk of developing drug resistance.

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Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

Cited by 29 publications

References 67 publications

Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies

Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies

Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma

Histone deacetylase‐based dual targeted inhibition in multiple myeloma

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