scholarly journals HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3862
Author(s):  
Christian Mayr ◽  
Tobias Kiesslich ◽  
Sara Erber ◽  
Dino Bekric ◽  
Heidemarie Dobias ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Histone Deacetylases ◽  
Class I ◽  
In Vivo Evaluation ◽  
Tract Cancer

Inhibition of histone deacetylases (HDACs) is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. Therefore, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition into a panel of eight established BTC cell lines. The screening results indicate a heterogeneous expression of HDACs across the studied cell lines. We next tested the effect of six established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis on cell viability of BTC cells and found that the effect (i) is dose- and cell-line-dependent, (ii) does not correlate with HDAC isoform expression, and (iii) is most pronounced for romidepsin (a class I HDACi), showing the highest reduction in cell viability with IC50 values in the low-nM range. Further analyses demonstrated that romidepsin induces apoptosis in BTC cells, reduces HDAC activity, and increases acetylation of histone 3 lysine 9 (H3K9Ac). Similar to BTC cell lines, HDAC 1/2 proteins were heterogeneously expressed in a cohort of resected BTC specimens (n = 78), and their expression increased with tumor grading. The survival of BTC patients with high HDAC-2-expressing tumors was significantly shorter. In conclusion, HDAC class I inhibition in BTC cells by romidepsin is highly effective in vitro and encourages further in vivo evaluation in BTC. In situ assessment of HDAC 2 expression in BTC specimens indicates its importance for oncogenesis and/or progression of BTC as well as for the prognosis of BTC patients.

Two novel histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 are active against biliary tract cancer and potentiate the efficacy of gemcitabine

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4149-4149 ◽  
Author(s):  
M. Wiedmann ◽  
T. Bluethner ◽  
M. Niederhagen ◽  
K. Schoppmeyer ◽  
J. Moessner ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Histone Deacetylase Inhibitors ◽  
Tract Cancer ◽  
Mib 1

4149 Background: Chromatin remodelling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. NVP-LAQ824 and NVP-LBH589 are two novel chemical entities belonging to a cinnamic hydroxamic acid class of compounds. Little is known about their efficacy for the treatment of biliary tract cancer. Methods: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for p21WAF-1, acH3Lys9 and acH4, cell cycle analysis, PARP assay, TUNEL assay, and immunhistochemistry for MIB-1. Results: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines (mean IC50 (3d) 0.08 and 0.04 μM, respectively) and was associated with hyperacetylation of nucleosomal histones H3 and H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and induction of apoptosis (PARP cleavage). After 28 d, NVP-LBH589 reduced tumor mass by 66% (bile duct cancer) and 87% (gallbladder cancer) in vivo in comparison to placebo and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis (TUNEL) and reduced cell proliferation (MIB-1). Conclusions: Our findings suggest that NVP-LBH589 > NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended. No significant financial relationships to disclose.

scholarly journals Targeting Interleukin-4 Receptor Alpha by Hybrid Peptide for Novel Biliary Tract Cancer Therapy

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Kahori Seto ◽  
Junichi Shoda ◽  
Tomohisa Horibe ◽  
Eiji Warabi ◽  
Masayuki Kohno ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cytotoxic Activity ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Interleukin 4 ◽  
Hybrid Peptide ◽  
Tract Cancer ◽  
Interleukin 4 Receptor

It is known that the interleukin-4 receptorα(IL-4Rα) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4Rα-lytic hybrid peptide composed of binding peptide to IL-4Rαand cell-lytic peptide and reported that the designed IL-4Rα-lytic hybrid peptide exhibited cytotoxic and antitumor activity bothin vitroandin vivoagainst the human pancreatic cancer cells expressing IL-4Rα. Here, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC). The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50) as low as 5 μM. We also showed that IL-4Rα-lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activityin vitro. In addition, intravenous administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTCin vivo. Taken together, these results indicated that the IL-4Rα-lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC.

scholarly journals Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

2020 ◽  
Vol 52 (3) ◽  
pp. 945-956 ◽  
Author(s):  
Ah-Rong Nam ◽  
Mei-Hua Jin ◽  
Ju-Hee Bang ◽  
Kyoung-Seok Oh ◽  
Hye-Rim Seo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Biliary Tract ◽  
Mtt Assay ◽  
Combination Treatment ◽  
Biliary Tract Cancer ◽  
Ataxia Telangiectasia ◽  
Cancer Drug ◽  
Ataxia Telangiectasia Mutated ◽  
Tract Cancer

PurposeCurrently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC.Materials and MethodsIn this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models.ResultsAZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy.ConclusionTaken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

Radiosensitivity of human biliary tract cancer cell lines in vitro

1997 ◽  
Author(s):  
Y Moon ◽  
W Dahlberg ◽  
Y Yu ◽  
T Ohno ◽  
T Todoroki ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Cancer Cell Lines ◽  
Tract Cancer

scholarly journals Impact of RARα and miR-138 on retinoblastoma etoposide resistance

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 11-26
Author(s):  
Maike Busch ◽  
Natalia Miroschnikov ◽  
Jaroslaw Thomas Dankert ◽  
Marc Wiesehöfer ◽  
Klaus Metz ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Lines ◽  
Cancer Progression ◽  
Treated Patient ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Gene Assay ◽  
The Impact

BACKGROUND: Retinoblastoma (RB) is the most common childhood eye cancer. Chemotherapeutic drugs such as etoposide used in RB treatment often cause massive side effects and acquired drug resistances. Dysregulated genes and miRNAs have a large impact on cancer progression and development of chemotherapy resistances. OBJECTIVE: This study was designed to investigate the involvement of retinoic acid receptor alpha (RARα) in RB progression and chemoresistance as well as the impact of miR-138, a potential RARα regulating miRNA. METHODS: RARα and miR-138 expression in etoposide resistant RB cell lines and chemotherapy treated patient tumors compared to non-treated tumors was revealed by Real-Time PCR. Overexpression approaches were performed to analyze the effects of RARα on RB cell viability, apoptosis, proliferation and tumorigenesis. Besides, we addressed the effect of miR-138 overexpression on RB cell chemotherapy resistance. RESULTS: A binding between miR-138 and RARα was shown by dual luciferase reporter gene assay. The study presented revealed that RARα is downregulated in etoposide resistant RB cells, while miR-138 is endogenously upregulated. Opposing RARα and miR-138 expression levels were detectable in chemotherapy pre-treated compared to non-treated RB tumor specimen. Overexpression of RARα increases apoptosis levels and reduces tumor cell growth of aggressive etoposide resistant RB cells in vitro and in vivo. Overexpression of miR-138 in chemo-sensitive RB cell lines partly enhances cell viability after etoposide treatment. CONCLUSIONS: Our findings show that RARα acts as a tumor suppressor in retinoblastoma and is downregulated upon etoposide resistance in RB cells. Thus, RARα may contribute to the development and progression of RB chemo-resistance.

The irreversible pan-HER inhibitor PF00299804 alone or combined with gemcitabine has an antitumor effect in biliary tract cancer cell lines

2011 ◽  
Vol 30 (6) ◽  
pp. 2148-2160 ◽  
Author(s):  
Hyun-Jin Nam ◽  
Hwang-Phill Kim ◽  
Young-Kwang Yoon ◽  
Sang-Hyun Song ◽  
Ah-Rum Min ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Antitumor Effect ◽  
Cancer Cell Lines ◽  
Tract Cancer

scholarly journals SHC014748M, a Novel Selective Inhibitor of PI3Kδ, Demonstrates Promising Pre-Clinical Antitumor Activity in B Cell Lymphomas and CLL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5306-5306
Author(s):  
Lei Fan ◽  
Chao Wang ◽  
Zhiqiang Wang ◽  
Xian Zhang ◽  
Lei Cao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Cell Lines ◽  
Xenograft Model ◽  
Selective Inhibitor ◽  
Lymphoma Cell ◽  
Class I ◽  
B Cell Lymphomas

Introduction : PI3Kδ, one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. Here, we comprehensively evaluated the in vitro and in vivo antitumor activity and the underlying mechanism of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Methods : Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary CLL cells, and PI3K/AKT pathway was measured by Western blot assay, Alphalisa and Elisa. Xenograft model was carried out to validate in-vivo antitumor potency of the compound. Besides, chemokines and cytokines derived from blood samples of patients were also detected. Results: SHC014748M was 125- to 306-fold more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines. We identified that SHC014748M treatment resulted in a 3.1- to 5.5-fold increase in annexin V/7-ADD staining, indicating a significant apoptosis induction. SHC014748M inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in lymphoma cells. Among the 15 primary CLL cells, the 50% inhibitory concentration (IC50) of SHC014748M varies from 850 nM to 37040 nM respectively and expression of phosphorylation AKT decreased to the normal levels in the presence of SHC014748M or positive control, Idelalisib. In-vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 derived from patients decreased sharply after SHC014748M treatment. Conclusion: According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL. Disclosures Wang: Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment. Wang:Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment. Zhang:Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment.

scholarly journals Evaluation of chidamide and PFI-1 as a combination therapy for triple-negative breast cancer

2020 ◽  
Vol 19 (2) ◽  
pp. 259-264
Author(s):  
Nong Lin ◽  
Qiaolu Yang ◽  
Tong Xu ◽  
Lianguo Shi
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Cell Viability ◽  
Breast Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Histone Deacetylases ◽  
Triple Negative ◽  
Inhibitory Effect

Purpose: To evaluate the in vitro and in vivo effects of the combination therapy of histone deacetylases (HDAsC) inhibitor, chidamide, and bromodomain-containing proteins (BETs) inhibitor, PFI-1, on triplenegative breast cancer (TNBC). Methods: Four distinct breast cancer cell lines and one TNBC mouse model were treated with vehicle, chidamide, PFI-1 alone, or chidamide and PFI-1. The inhibitory effect of chidamide or PFI-1 on HDACs and BETs was assessed by HDAC enzyme inhibition and AlphaScreen assays. Cell viability was determined by MTT assay while protein expression of p-STAT3 was evaluated by western blotting and immunohistochemistry (IHC) staining assay. Results: Chidamide exerted inhibitory effect on HDACs while PFI-1 inhibited BET proteins. The threedimensional model demonstrated the interactions between chidamide and HDAC2, and between PFI-1 and BRD4. Chidamide or PFI-1 exerted inhibitory effects on breast cancer cell proliferation in vitro. However, the combination of PFI-1 and chidamide significantly inhibit MDA-MB-231 cell viability, and decrease the expression of p-STAT3, when compared to that treated with chidamide or PFI-1 alone. Moreover, the combined inhibitory effect of PFI-1 and chidamide on tumor growth was also found in the in vivo mice experiments. Conclusion: The combination of chidamide and PFI-1 is a potential is a potential therapeutic strategy for the management of TNBC. Keywords: Triple-negative breast cancer, Histone deacetylases, Bromodomain

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