Antitumor activity of suberoylanilide hydroxamic acid against human oral squamous cell carcinoma cell lines in vitro and in vivo

Nagumo, Tatsuhito; Takaoka, Sayaka; Yoshiba, Sayaka; Ohashi, Masaru; Shirota, Tatsuo; Hatori, Masahito; Isobe, Tomohide; Tachikawa, Tetsuhilco; Shintani, Satoru

doi:10.1016/j.oraloncology.2008.11.009

Cited by 15 publications

(8 citation statements)

References 22 publications

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“…SAHA inhibits the class I HDACs (HDAC1, HDAC2, HDAC3) and the class II HDACs (HDAC6) and under the trade name Zolinza® was the first histone deacetylase inhibitor approved by FDA for clinical use in cutaneous T cell lymphoma (CTCL) 31, 32. SAHA is a compound with low toxicity in normal cells 33, which was also confirmed in the current study, and high therapeutic potential for different tumors including colon cancer 34, prostate cancer 35, breast cancer 36, non-small cell lung cancer 37, pancreatic cancer 38, glioma cells 39, uterine sarcoma 40, ovarian cancer 41 and oral squamous cell carcinoma 42. In the present study, we showed that SAHA suppressed the growth of larynx cancer cell lines at micromolar concentrations in a dose-dependent manner.…”

Section: Discussionsupporting

confidence: 79%

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

et al. 2017

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Objective: Laryngeal squamous cell carcinoma is one of the most common malignant tumors in the head and neck region. Due to the poor response to chemotherapeutics in patients and low survival rate, successful treatment of larynx cancer still remains a challenge. Therefore, the identification of novel treatment options is needed. We investigated the anticancer effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on two different laryngeal cancer cell lines RK33 and RK45. We also studied the antiproliferative action of SAHA in combination with cisplatin and defined the type of pharmacological interaction between these drugs. Materials and Methods: Viability and proliferation of larynx cancer cell lines were studied by methylthiazolyldiphenyl-tetrazolium bromide method and 5-bromo-2-deoxyuridine incorporation assay, respectively. The type of interaction between SAHA and cisplatin was determined by an isobolographic analysis. Western blotting, flow cytometry and quantitative polymerase chain reaction method were used to determine acetylation of histone H3, cell cycle progression and genes expression, respectively. Apoptosis was assessed by means of nucleosomes released to cytosol. Results: SAHA alone or in combination with cisplatin inhibited larynx cancer cells proliferation, whereas displayed relatively low toxicity against normal cells -primary cultures of human skin fibroblasts. The mixture of SAHA with cisplatin exerted additive and synergistic interaction in RK33 and RK45 cells, respectively. We showed that SAHA induced hyperacetylation of histone H3 K9, K14 and K23 and triggered apoptosis. SAHA also caused cell cycle arrest by upregulation of CDKN1A and downregulation of CCND1 encoding p21WAF1/CIP1 and cyclin D1 proteins, respectively. Conclusion: Our studies demonstrated that SAHA may be considered as a potential therapeutic agent against larynx tumors.

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Section: Discussionsupporting

confidence: 79%

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

et al. 2017

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“…Generally, similar with the effects induced by HDACi in other cancers, these chemical compounds impaired cell growth as well as induced cell apoptosis and senescence in tongue cancer. 49,50 Moreover, HDACi exposure also significantly reduced cell colony formation and CD44 þ CD133 þ cell fraction, and enhanced cisplatin sensitivity in tongue cancer cells. These phenotypic alternations induced by HDACi largely phenocopied the Bmi1 knockdown.…”

Section: Discussionmentioning

confidence: 95%

Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer

Wang

Yuan

et al. 2014

Laboratory Investigation

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The polycomb complex protein Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog) mediates epigenetic transcriptional silencing by modifying chromatin structure and is critical for stem cell homeostasis and tumorigenesis. Bmi1 is frequently overexpressed in human malignancies and therefore has key diagnostic and prognostic significance, and holds potential as a therapeutic target. Here we sought to characterize the expression patterns and oncogenic roles of Bmi1 in tongue squamous cell carcinoma and to determine the anticancer effects of histone deacetylase inhibitors (HDACis) via Bmi1 inhibition against tongue cancer. Our data revealed that Bmi1 was aberrantly overexpressed in a significant portion of tongue cancers. Elevated Bmi1 is associated with cervical node metastasis, Ki-67 abundance and reduced overall survival, and also serves as an independent prognostic factor for patient outcomes. Short-hairpin RNA-mediated Bmi1 knockdown inhibited cell proliferation and migration, induced cell apoptosis and senescence, reduced colony formation and CD44þ CD133 þ sub-population as well as enhanced cisplatin chemosensitivity, presumably by modulation of p16, p14 and E-cadherin. Moreover, HDACi chemicals Trichostatin A (TSA) and sodium butyrate (NaB) potently inhibited Bmi1 and triggered similar phenotypic changes reminiscent of Bmi1 silencing, although TSA treatment seemed paradoxically to induce some epithelial-mesenchymal transition-like changes in tongue cancer cells. Importantly, NaB-induced antitumor effects were partially attenuated by enforced Bmi1 overexpression in vitro. Genetic Bmi1 silencing and pharmacological inhibition of Bmi1 by NaB treatment significantly impaired tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that Bmi1 serves as a key driver and biomarker with multiple oncogenic functions underlying tongue tumorigenesis. Selected appropriate HDACi compounds like NaB may represent novel therapeutic agents against tongue cancer. Oral cancer is one of the most common cancers worldwide, approximately accounting for 3% of all malignancies in both sexes. It is widely represented as a heterogeneous tumor with aggressive phenotypes and behaviors. The major etiological risks for this malignancy include smoking and alcohol consumption and human papillomavirus infection. 1 The overwhelming majority of oral cancers arises from tongue and is pathologically identified as squamous cell carcinoma (SCC). 2 Despite tremendous advancement in multimodal therapies against oral cancers over the past decades, the overall 5-year survival rate with these devastating diseases, especially those with advanced diseases, has not been markedly improved. 3 Local relapse and cervical lymph node metastasis are recognized as the most prevalent factors affecting patients' survival. Although many oncogenes and tumor suppressors have been identified as key factors underlying oral tumorigenesis, however, no optimal and commonly accepted biomarkers have been established to facilitate disease diagnosis, ...

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“…Group 5 was immunized and treated with romidepsin intraperitoneally (ip) twice a week at 1.5 mg/kg per dose, similarly to what has been described previously [33-35]. Group 6 was immunized and treated with SAHA (IC50 = 26 nM ) per oral at 30 mg/kg per dose, similarly to what has been described previously [36-38]. Mice were monitored twice a week by inspection and palpation.…”

Section: Methodsmentioning

confidence: 99%

Histone deacetylase inhibitor AR-42 enhances E7-specific CD8+ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination

et al. 2013

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We have previously created a potent DNA vaccine encoding calreticulin linked to the HPV oncogenic protein E7 (CRT/E7). While treatment of the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency of the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi have been shown to increase the expression of MHC class I and II molecules. Thus, we aimed to determine whether co-administration of a novel HDACi, AR-42, with therapeutic HPV DNA vaccines could improve activation of HPV antigen-specific CD8+ T cells resulting in potent therapeutic antitumor effects. To do so, HPV-16 E7-expressing murine TC-1 tumor-bearing mice were treated orally with AR-42 and/or CRT/E7 DNA vaccine via gene gun. Mice were monitored for E7-specific CD8+ T cell immune responses and antitumor effects. TC-1 tumor-bearing mice treated with AR-42 and CRT/E7 DNA vaccine experienced longer survival, decreased tumor growth, and enhanced E7-specific immune response compared to mice treated with AR-42 or CRT/E7 DNA vaccine alone. Additionally, treatment of TC-1 cells with AR-42 increased surface expression of MHC class I molecules and increased the susceptibility of tumor cells to the cytotoxicity of E7-specific T cells. This study indicates the ability of AR-42 to significantly enhance the potency of the CRT/E7 DNA vaccine by improving tumor-specific immune responses and antitumor effects. Both AR-42 and CRT/E7 DNA vaccine have been used in independent clinical trials and the current study serves as foundation for future clinical trials combining both treatments in cervical cancer therapy.

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Antitumor activity of suberoylanilide hydroxamic acid against human oral squamous cell carcinoma cell lines in vitro and in vivo

Cited by 15 publications

References 22 publications

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer

Histone deacetylase inhibitor AR-42 enhances E7-specific CD8+ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination

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