OBP‑801, a novel histone deacetylase inhibitor, induces M‑phase arrest and apoptosis in rhabdomyosarcoma cells

Tomoyasu, Chihiro; Kikuchi, Ken; Kaneda, Daisuke; Yagyu, Shigeki; Miyachi, Mitsuru; Tsuchiya, Kunihiko; Iehara, Tomoko; Sakai, Toshiyuki; Hosoi, Hajime

doi:10.3892/or.2018.6813

Cited by 5 publications

(16 citation statements)

References 32 publications

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“…It is well known that HDAC inhibitors induce cell death such as mitochondria-mediated apoptosis in many cancer cells (17,18,20,34). Several reports have demonstrated that OBP-801 induces caspasedependent apoptosis in some cancers (24,35). In our study, rhabdoid tumor cell lines exhibited caspase-dependent apoptosis by OBP-801, like reported for other cancers.…”

Section: Discussionsupporting

confidence: 85%

“…There are still challenges regarding the clinical application of OBP-801 in humans, because OBP-801 is a novel agent, and experimental data on its use in humans are scarce. However, in this study, the efficacy of OBP-801 was confirmed at a lower dose than previously used in our experiments on xenograft mouse models, and no serious adverse events were identified (24,35).…”

Section: Discussionsupporting

confidence: 62%

“…In rhabdoid tumors, several tumor suppressor genes including p21 are responsible for oncogenic mechanisms (13). OBP-801 activates the P21-RB pathway via p21 induction in certain cancers (24). First, we hypothesized that OBP-801 would be an optimal drug for rhabdoid tumor treatment, because OBP-801 induces p21 that is an important gene for the aberrant rhabdoid tumor cell cycle.…”

Section: Discussionmentioning

confidence: 99%

“…Protein extraction and Western blotting were performed in rhabdoid tumor cell lines as described previously (24). In the experiments using OBP-801, proteins were extracted 24 hours after the administration of OBP-801 or vehicle.…”

Section: Protein Extracts and Western Blottingmentioning

confidence: 99%

“…Through "drug screening for reactivation of RB," OBP-801 (YM753/spiruchostatin A) was discovered to be a novel HDAC inhibitor that upregulates p21 gene expression (20). OBP-801 has shown efficacy against various cancer types (21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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The Novel Histone Deacetylase Inhibitor, OBP-801, Induces Apoptosis in Rhabdoid Tumors by Releasing the Silencing of NOXA

Sugimoto

Katsumi

Iehara

et al. 2020

Molecular Cancer Therapeutics

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Rhabdoid tumor is an aggressive, early childhood tumor. Biallelic inactivation of the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1)/integrase interactor 1 (INI1) gene is the only common genetic feature in rhabdoid tumors. Loss of SMARCB1 function results in downregulation of several tumor suppressor genes including p16, p21, and NOXA. The novel histone deacetylase inhibitor, OBP-801, induces p21 and has shown efficacy against various cancers. In our study, OBP-801 strongly inhibited the cell growth of all rhabdoid tumor cell lines in WST-8 assay. However, Western blotting and cell-cycle analysis revealed that OBP-801 did not activate the P21-RB pathway in some cell lines. p21 knockout indicated that p21 did not dominate the OBP-801 antitumor effect in rhabdoid tumor cell lines. We discovered that OBP-801 induced NOXA expression and caspase-dependent apoptosis in rhabdoid tumor cell lines independent of TP53.Chromatin immunoprecipitation assay showed that OBP-801 acetylated histone proteins and recruited RNA polymerase II to the transcription start site (TSS) of the NOXA promotor. Moreover, OBP-801 recruited BRG1 and BAF155, which are members of the SWI/SNF complex, to the TSS of the NOXA promotor. These results suggest that OBP-801 epigenetically releases the silencing of NOXA and induces apoptosis in rhabdoid tumors. OBP-801 strongly inhibited tumor growth in human rhabdoid tumor xenograft mouse models in vivo. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and cleaved caspase-3 were stained in tumors treated with OBP-801. In conclusion, OBP-801 induces apoptosis in rhabdoid tumor cells by epigenetically releasing the silencing of NOXA, which is a key mediator of rhabdoid tumor apoptosis. The epigenetic approach for NOXA silencing with OBP-801 is promising for rhabdoid tumor treatment.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Protein Extracts and Western Blottingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Novel Histone Deacetylase Inhibitor, OBP-801, Induces Apoptosis in Rhabdoid Tumors by Releasing the Silencing of NOXA

Sugimoto

Katsumi

Iehara

et al. 2020

Molecular Cancer Therapeutics

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Assessment of Synergistic Contribution of Histone Deacetylases in Prognosis and Therapeutic Management of Sarcoma

et al. 2020

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Sarcomas are a rare group of neoplasms with a mesenchymal origin that are mainly characterized by the abnormal growth of connective tissue cells. The standard treatment for local control of sarcomas includes surgery and radiation, while for adjuvant and palliative therapy, chemotherapy has been strongly recommended. Despite the availability of multimodal therapies, the survival rate for patients with sarcoma is still not satisfactory. In recent decades, there has been a considerable effort to overcome chemotherapy resistance in sarcoma cells. This has led to the investigation of more cellular compounds implicated in gene expression and transcription processes. Furthermore, it has been discovered that histone acetylation/deacetylation equilibrium is affected in carcinogenesis, leading to a modified chromatin structure and therefore changes in gene expression. In addition, histone deacetylase inhibition is found to play a key role in limiting the tumor burden in sarcomas, as histone deacetylase inhibitors act on well-described oncogenic signaling pathways. Histone deacetylase inhibitors disrupt the increased cell motility and invasiveness of sarcoma cells, undermining their metastatic potential. Moreover, their activity on evoking cell arrest has been extensively described, with histone deacetylase inhibitors regulating the reactivation of tumor suppressor genes and induction of apoptosis. Promoting autophagy and increasing cellular reactive oxygen species are also included in the antitumor activity of histone deacetylase inhibitors. It should be noted that many studies revealed the synergy between histone deacetylase inhibitors and other drugs, leading to the enhancement of an antitumor effect in sarcomas. Therefore, there is an urgent need for therapeutic interventions modulated according to the distinct clinical and molecular characteristics of each sarcoma subtype. It is concluded that a better understanding of histone deacetylase and histone deacetylase inhibitors could provide patients with sarcoma with more targeted and efficient therapies, which may contribute to significant improvement of their survival potential.

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The histone deacetylase inhibitor OBP‐801 has in vitro/in vivo anti‐neuroblastoma activity

Kaneda

Iehara

Kikuchi

et al. 2022

Pediatrics International

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Background Patients with high‐risk neuroblastoma have a poor prognosis; new therapeutic agents are therefore required. We investigated the antitumor effects of OBP‐801, a novel histone deacetylase inhibitor, its underlying mechanism, and its potential as a therapeutic agent for patients with neuroblastoma. Methods The study included five human neuroblastoma cell lines: IMR32, GOTO, KP‐N‐RTBM, SK‐N‐AS, and SH‐SY5Y. We investigated cell proliferation, cell cycle status, protein expression patterns, and apoptosis in neuroblastoma cells after OBP‐801 treatment in vitro. Cell survival rate and cell cycle were analyzed using the WST‐8 assay and flow cytometry, respectively. Apoptosis was detected using annexin V staining, and the expression of apoptosis‐related proteins was investigated by western blotting. The antitumor activity of OBP‐801 was examined in an in vivo xenograft mouse model. Results Dose–effect curve analysis showed that the mean half‐maximal inhibitory concentration value was 5.5 ± 5.9 nM for the MYCN‐amplified cell lines (IMR32, GOTO, and KP‐N‐RTBM) and 3.1 ± 0.7 nM for the MYCN‐nonamplified cell lines (SK‐N‐AS and SH‐SY5Y). OBP‐801 inhibited cell proliferation and growth in all the cell lines. It induced G2/M phase arrest through the p21 (CDKN1A) pathway, increasing histone H3 levels and, subsequently, apoptosis in human neuroblastoma cells. OBP‐801 suppressed the growth of neuroblastoma cells in the mouse xenograft model. Conclusions Overall, OBP‐801 induces M‐phase arrest and apoptosis in neuroblastoma cells via mitotic catastrophe. Our results indicate that OBP‐801 is a promising therapeutic agent with fewer adverse effects for patients with neuroblastoma.

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OBP‑801, a novel histone deacetylase inhibitor, induces M‑phase arrest and apoptosis in rhabdomyosarcoma cells

Cited by 5 publications

References 32 publications

The Novel Histone Deacetylase Inhibitor, OBP-801, Induces Apoptosis in Rhabdoid Tumors by Releasing the Silencing of NOXA

The Novel Histone Deacetylase Inhibitor, OBP-801, Induces Apoptosis in Rhabdoid Tumors by Releasing the Silencing of NOXA

Assessment of Synergistic Contribution of Histone Deacetylases in Prognosis and Therapeutic Management of Sarcoma

The histone deacetylase inhibitor OBP‐801 has in vitro/in vivo anti‐neuroblastoma activity

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