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.

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

Killing effects of 5-fluorouracil on human biliary tract cancer cell lines.

1999 ◽  
Author(s):  
Y Moon ◽  
T Todoroki ◽  
T Ohno ◽  
K Fukao ◽  
J B Little
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Cancer Cell Lines ◽  
Tract Cancer

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.

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 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

Abstract 3401: Genomic and transcriptome profile of 66 Chinese biliary tract cancer patient derived cell lines

2019 ◽  
Author(s):  
Feiling Feng ◽  
Qingbao Cheng ◽  
Bin Li ◽  
Liang Yang ◽  
Hua Dong ◽  
...  
Keyword(s):  
Cancer Patient ◽  
Cell Lines ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Transcriptome Profile ◽  
Tract Cancer

Abstract 3401: Genomic and transcriptome profile of 66 Chinese biliary tract cancer patient derived cell lines

2019 ◽  
Author(s):  
Feiling Feng ◽  
Qingbao Cheng ◽  
Bin Li ◽  
Liang Yang ◽  
Hua Dong ◽  
...  
Keyword(s):  
Cancer Patient ◽  
Cell Lines ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Transcriptome Profile ◽  
Tract Cancer

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.

Different expression pattern of stem cell markers in xenografts of human biliary tract cancer cell lines

2011 ◽  
Vol 49 (01) ◽  
Author(s):  
T Kiesslich ◽  
B Alinger ◽  
R Kemmerling ◽  
M Ocker ◽  
F Berr ◽  
...  
Keyword(s):  
Stem Cell ◽  
Expression Pattern ◽  
Cell Lines ◽  
Cancer Cell ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Cancer Cell Lines ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Tract Cancer

Downregulation of SPARC Is Associated with Epithelial-Mesenchymal Transition and Low Differentiation State of Biliary Tract Cancer Cells

2019 ◽  
Vol 60 (1-2) ◽  
pp. 1-12
Author(s):  
Ughur Aghamaliyev ◽  
Haristi Gaitantzi ◽  
Maria Thomas ◽  
Katja Simon-Keller ◽  
Timo Gaiser ◽  
...  
Keyword(s):  
Cell Lines ◽  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Transforming Growth Factor ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Desmoplastic Reaction ◽  
Tract Cancer ◽  
Sparc Expression ◽  
E Cadherin

Background: Biliary tract cancers (BTCs) have a poor prognosis. BTCs are characterized by a prominent desmoplastic reaction which possibly contributes to the aggressive phenotype of this tumor. The desmoplastic reaction includes excessive production and deposition of extracellular matrix proteins such as periostin, secreted protein acidic and rich in cysteine (SPARC), thrombospondin-1, as well as accumulation of α-smooth muscle actin-positive cancer-associated fibroblasts and immune cells, secreting growth factors and cytokines including transforming growth factor (TGF)-β. In the present study, we investigated the expression of SPARC in BTC as well as its possible regulation by TGF-β. Methods: Expression levels of Sparc, TGF-β1 and its receptor ALK5 were evaluated by quantitative real-time PCR in 6 biliary tract cell lines as well as 1 immortalized cholangiocyte cell line (MMNK-1). RNAs from tumor samples of 7 biliary tract cancer patients were analyzed for expression of Sparc, TGF-β type II receptor (TbRII) as well as Twist and ZO-1. MMNK-1 cells were stimulated with TGF-β for 24 h, and Sparc, ZO-1 and E-Cadherin expressions were determined. The presence of SPARC protein was analyzed by immunohistochemistry in tumor specimens from 10 patients. Results: When comparing basal Sparc transcript levels in diverse BTC cell lines to MMNK-1 cells, we found that it was strongly downregulated in all cancer cell lines. The remaining expression levels were higher in highly differentiated cell lines (CCSW1, MZChA1, MZChA2 and TFK-1) than in less differentiated and undifferentiated ones (BDC, SKChA1). Expression of Sparc in BTC patient samples showed a significant positive correlation with expression of the epithelial marker ZO-1. In contrast, the mesenchymal marker Twist and the TbRII showed a trend of negative correlation with expression of Sparc in these samples. TGF-β exposure significantly downregulated Sparc expression in MMNK-1 cholangiocytes in vitro in parallel to downregulation of epithelial markers (E-Cadherin and ZO-1). Finally, SPARC immunostaining was performed in 10 patient samples, and the correlation between absence of SPARC and survival times was analyzed. Conclusions: These data imply that a decrease in SPARC expression is correlated with dedifferentiation of BTC cells resulting in enhanced EMT being possibly mediated by TGF-β. Thereby SPARC levels might be a marker for individual prognosis of a patient, and strategies aiming at inhibition of SPARC downregulation might have potential for new future therapies.

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