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.

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.

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

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 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 Synergistic and Pharmacotherapeutic Effects of Gemcitabine and Cisplatin Combined Administration on Biliary Tract Cancer Cell Lines

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1026 ◽  
Author(s):  
Yasunari Sakamoto ◽  
Seri Yamagishi ◽  
Takuji Okusaka ◽  
Hidenori Ojima
Keyword(s):  
Cell Lines ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Synergistic Effects ◽  
Resistant Cell ◽  
Molar Ratio ◽  
Additive Effects ◽  
Tract Cancer ◽  
Ic50 Values ◽  
Renal Clearances

Gemcitabine (GEM) and cisplatin (CDDP) combination therapy (GC) is the standard chemotherapy for advanced biliary tract cancer (BTC); however, its pharmacotherapeutic efficacy remains unclear. To investigate the effects of GC, we selected 11 from 17 BTC cell lines, according to their GEM sensitivity, to be assessed using the MTS assay. The presence of synergistic effects of GC was determined using the Bliss additivism model (BM) and the combination index (CI) at a GEM:CDDP molar ratio of 7:1; this ratio was based on the respective human renal clearances of the two drugs. The pharmacotherapeutic effects were evaluated by comparing the IC50 values for administrations of GEM alone and GC in combination. All cell lines showed synergistic effects when analyzed using the BM. Based on the CI values, strong synergism, synergism, and additive effects were seen in four, five, and two cell lines, respectively. For all four GEM-resistant cell lines, on which GC had strong synergistic effects, the pharmacotherapeutic effects of GC were disappointing, with all IC50 values > 1 µM. For the GEM-effective cell lines, on which GC had synergistic or additive effects, the IC50 values were all <1 µM, and the differences were small between the IC50s for administration of GEM alone and GC in combination. Our results suggest that GC has synergistic effects on BTC cell lines but that its pharmacotherapeutic effects are inadequate.

scholarly journals Establishment and characterisation of six human biliary tract cancer cell lines

2002 ◽  
Vol 87 (2) ◽  
pp. 187-193 ◽  
Author(s):  
J-L Ku ◽  
K-A Yoon ◽  
I-J Kim ◽  
W-H Kim ◽  
J-Y Jang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Cancer Cell Lines ◽  
Tract Cancer
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