Epigenetic Modulation of Retinoic Acid Receptor β2 by the Histone Deacetylase Inhibitor MS-275 in Human Renal Cell Carcinoma

Wang, Xiao Fei; Qian, David Z.; Ren, Mingqiang; Kato, Yukihiko; Wei, Yongfeng; Zhang, Lu; Fansler, Zoya; Clark, Douglas B.; Nakanishi, Osamu; Пили, Роберто

doi:10.1158/1078-0432.ccr-04-1092

Cited by 74 publications

(64 citation statements)

References 34 publications

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“…MS-275 has also shown inhibition of tumor cell growth in nude mice that was comparable or superior to conventional cytotoxic agents. Our group has previously reported that MS-275 has a significant antitumor activity in a renal cell carcinoma model (14). The results from a phase I testing of MS-275 have also been recently reported (15).…”

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confidence: 74%

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Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma

Kato

Yoshimura

Shin³

et al. 2007

Clinical Cancer Research

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Purpose: High-dose interleukin 2 (IL-2) is a Food and Drug Administration^approved regimen for patients with metastatic renal cell carcinoma. However, the toxicity and limited clinical benefit associated with IL-2 has hampered its use. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor models including renal cell carcinoma, and to have immunomodulatory properties. In our study, we tested the effectiveness of combination therapy of IL-2 with the HDAC inhibitor MS-275 in a murine renal cell carcinoma (RENCA) model. Experimental Design: RENCA luciferase^expressing cells were implanted in the left kidney of BALB/C mice. Animals were randomly divided into four groups and treated with either vehicle, 150,000 IU of IL-2 twice daily by i.p. injections (twice weekly), 5 mg/kg of MS-275 daily by oral gavage (5 d/wk), or its combination.Treatment was started either 3 or 9 days following tumor cell injection. Results: Weekly luciferase images and tumor weight after 2 weeks of treatment showed significant tumor inhibition (>80%) in the combination treatment as compared with the IL-2 (no significant inhibition) or MS-275 (f40% inhibition) treatment groups. Spontaneous lung metastases were also inhibited in the combination treatment (>90% inhibition) as compared with the single treatment group. Kaplan-Meier analyses showed statistically significant increased survival in the combination group as compared with controls and single agents. Splenocytes from mice treated with combination treatment showed greater lysis of RENCA cells than splenocytes from mice treated with single agents. The percentage of CD4 + CD25+ Tcells and Foxp3 + T cells (T regulatory cells) was increased or reduced, respectively, in lymph nodes from tumor-bearing animals treated with the combination of MS-275 and IL-2 as compared with control and single agents. Depletion of CD8 + T cells abrogated the survival benefit from MS-275 + IL-2 combination. Conclusions: These results show that the combination of IL-2 and MS-275 has a synergistic antitumor effect in vivo in an immunocompetent murine model of renal cell carcinoma. The antitumor effect was associated with the decreased number of T regulatory cells and the increased antitumor cytotoxicity by splenocytes. In conclusion, these preclinical data provide the rationale for clinical testing of the combination of IL-2 and HDAC inhibitors in the treatment of patients with renal cell carcinoma.

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confidence: 74%

“…On day 1, cells were incubated in RPMI (5% serum) with increasing concentrations of MS-275 and/or IL-2. IL-2 and MS-275 concentrations for in vitro studies were chosen based on published reports (13,14,22). XTT assay was done on day 1 (as T = 0) reading and on day 4 (T = 72 h) according to the manufacturer's standard guidelines.…”

Section: Methodsmentioning

confidence: 99%

Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma

Kato

Yoshimura

Shin³

et al. 2007

Clinical Cancer Research

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“…Indeed, in several mouse xenograft studies involving renal cell carcinoma and neuroblastoma, synergistic tumor growth inhibition has been observed with HDACI plus retinoids (21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors

Epping

Wang

Plumb

et al. 2007

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

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Understanding the pathways that are targeted by cancer drugs is instrumental for their rational use in a clinical setting. Inhibitors of histone deacetylases (HDACI) selectively inhibit proliferation of malignant cells and are used for the treatment of cancer, but their cancer selectivity is understood poorly. We conducted a functional genetic screen to address the mechanism(s) of action of HDACI. We report here that ectopic expression of two genes that act on retinoic acid (RA) signaling can cause resistance to growth arrest and apoptosis induced by HDACI of different chemical classes: the retinoic acid receptor ␣ (RAR␣) and preferentially expressed antigen of melanoma (PRAME), a repressor of RA signaling. Treatment of cells with HDACI induced RA signaling, which was inhibited by RAR␣ or PRAME expression. Conversely, RAR-deficient cells and PRAME-knockdown cells show enhanced sensitivity to HDACI in vitro and in mouse xenograft models. Finally, a combination of RA and HDACI acted synergistically to activate RA signaling and inhibit tumor growth. These experiments identify the RA pathway as a rate-limiting target of HDACI and suggest strategies to enhance the therapeutic efficacy of HDACI.biomarker ͉ chromatin modification ͉ drug resistance ͉ epigenetics ͉ nuclear hormone receptor E pigenetic DNA and histone modifications are appreciated as major determinants in the control of gene activity, and they are extensively deregulated in cancer. Histone acetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs), which catalyze the addition and removal of acetyl groups to histones, respectively, and to a growing list of nonhistone substrates (1). The activities of HATs and HDACs are altered in several human cancers, and modulation of these classes of enzymes provides a potentially attractive therapeutic modality (2, 3). Several classes of HDAC inhibitors (HDACI) have been identified that block enzyme activity, resulting in global histone hyperacetylation. A wide array of literature on HDACI exists, describing their various effects, including G 1 and G 2 /M cell cycle arrests, apoptosis, and differentiation, and several HDACI have entered clinical trials (2-4). Gene expression profiling studies revealed that HDACI treatment induces alterations in transcription of Ͻ5% to Ϸ20% of expressed genes (5, 6) and have not elucidated a consistent picture of the pathway(s) or target(s) that are modulated by HDACI and, consequently, have not provided a comprehensive explanation for their anticancer effects.To identify cellular targets of HDACI action in transformed cells, we used the approach of large-scale functional genetic screening. In this screen we asked which genes or pathways could confer cellular resistance to HDACI. The present work provides evidence that the retinoic acid receptor (RAR) pathway is targeted by HDACI and that the cytotoxic effects of HDACI in solid tumor cells are, at least in part, through derepression of retinoic acid (RA) signaling. ResultsGe...

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“…Chromatin Immunoprecipitation Assay The histone acetylation status of RARb2 promoter was examined using the chromatin immunoprecipitation assay as described previously (19). An antibody specific for acetylated histone 3 (H3) was used to immunoprecipitate formaldehyde cross-linked, sonicated chromatin from cells treated with LAQ824 or the combination.…”

Section: Colony Formation Assaymentioning

confidence: 99%

“…Quantitative real-time PCR for specific genes was done to confirm the differences in RARb gene expression identified by RT-PCR (19). Single-strand cDNA was synthesized from melanoma cell total RNA (1 Ag) by reverse transcription using oligo(dT) as the primer.…”

Section: Quantitative Real-time Pcr Analysismentioning

confidence: 99%

Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma

Kato

Salumbides

Wang

et al. 2007

Molecular Cancer Therapeutics

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Resistance to chemotherapy is a major hurdle in the treatment of malignant melanoma. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor types, including melanoma, and to reverse epigenetic repression of tumor suppressor genes, such as retinoic acid receptor b (RARb). In this study, we tested the antitumor effect of the HDAC inhibitor LAQ824 in combination with 13-cis-retinoic acid (CRA) on two human melanoma cell lines both in vitro and in vivo. Treatment of LAQ824 showed a dose-dependent inhibitory effect on A2058 and HMV-I cell lines in a clonogenic assay. These cell lines were relatively resistance to CRA. On treatment with combination of LAQ824 and CRA, a greater inhibitory effect (up to 98%) was achieved compared with single agents. Lack of RARb2 gene expression was associated with histone acetylation and gene methylation at the promoter level. Treatment with LAQ824 restored retinoid sensitivity by reverting RARb2 epigenetic silencing. The biological effect of LAQ824 was associated with p21 induction in both cell lines but G 2 cell cycle arrest in A2058 and apoptosis in HMV-I cell line. The induction of apoptosis by LAQ824 was associated with increased reactive oxygen species and induction of SM22 gene expression in HMV-I but not in A2058 cell line. Administration of the free radical scavenger L-N -acetylcysteine blocked LAQ824 + CRAmediated apoptosis in HMV-I cells, suggesting a primary role for reactive oxygen species generation in LAQ824 + CRA -associated lethality. Combination treatment showed 61% and 82% growth inhibition in A2058 and HMV-I tumors, respectively. Greater induction of in vivo apoptosis was observed in the HMV-I but not in the A2058 tumors treated with combination therapy compared with single agents. These results suggest that the HDAC inhibitor LAQ824 has a greater antitumor activity in combination with CRA in melanoma tumors but the degree of induced apoptosis may vary. Combination of HDAC inhibitors and retinoids represents a novel therapeutic approach for malignant melanoma that warrants clinical testing. [Mol Cancer Ther 2007;6(1):70 -81]

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Epigenetic Modulation of Retinoic Acid Receptor β2 by the Histone Deacetylase Inhibitor MS-275 in Human Renal Cell Carcinoma

Cited by 74 publications

References 34 publications

Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma

Synergistic In vivo Antitumor Effect of the Histone Deacetylase Inhibitor MS-275 in Combination with Interleukin 2 in a Murine Model of Renal Cell Carcinoma

A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors

Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma

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