Preferential chemosensitivity to gemcitabine by cyclin E overexpression in human gastric cancers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21020-21020
Author(s):  
K. Yeh ◽  
Y. Shen ◽  
Y. Chiang ◽  
P. Liu ◽  
C. Huang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Cyclin E ◽  
Parp Cleavage ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Gastric Cancers ◽  
Induced Apoptosis

21020 Background: Exploration of molecular determinants for chemosensitivity is the key element of personalized cancer therapy. Cyclin E is a major G1-phase cyclin, together with the CDK2, which mediates phosphorylation and functional inactivation of Rb protein. Cyclin E overexpression has been demonstrated in a variety of cancers, including human gastric cancers (GC), while its biologic significance in drug therapy remains unclear. Previously, we have demonstrated that cyclin D1 overexpression plays an important role in differential chemosensitivity of human GC cells (Proc Am Assoc Cancer Res 2004; 45: abstract 4888). In this study, we examine the roles between cyclin E overexpression and chemosensitivity of human GC cells. Methods: Compared human gastric cancer cells (NCI-N87) with stably transfected cells (N87-CyE), which have 2-fold overexpression of cyclin E, the IC50 for gemcitabine (2'-2'-difluoro- deoxycytidine, dFdC) was more than 1-log lower in N87-CyE (17.0 ± 2.7 nM) than N87 cells (113.7 ± 6.5 nM) by MTT colorimetric cytotoxicity assay. In contrast, the N87-CyE cells are only slightly more chemosensitive to taxanes (paclitaxel and docetaxel), and confer largely identical chemosensitivity to 5-FU, cisplatin, and irinotecan (CPT-11). We applied RNA interference (RNAi) of cyclin E to N87 cells. The stably transfected N87-CyE/RNAi cells readily confer gemcitabine resistance with the IC50 for gemcitabine of 124.5 ± 1.6 nM. Results: Gemcitabine-induced apoptosis in N87, N87-CyE, or N87-CyE/RNAi cells was shown in either caspase-3 or PARP (poly ADP-ribose polymerase) cleavage assay by Western blotting, and Annexin-V-FITC apoptosis detection by flowcytometry. The threshold concentration of gemcitabine for caspase-3 and PARP cleavage was 10–25 nM for N87-CyE, and 100–200 nM for N87 or N87-CyE/RNAi, respectively. Conclusions: Our data demonstrate that preferential chemosensitivity to gemcitabine by cyclin E overexpression in gastric cancer cells. Gemcitabine-induced apoptosis is enhanced by cyclin E overexpression, while is reduced by RNAi of cyclin E. Further studies for potential clinical use of gemcitabine in personalized chemotherapy for cyclin E or cyclin D1-overexpressing GC are warranted (supported by the grants of NHRI-CN-CA9201S, Taiwan). No significant financial relationships to disclose.

scholarly journals Flavokawain B and Doxorubicin Work Synergistically to Impede the Propagation of Gastric Cancer Cells via ROS-Mediated Apoptosis and Autophagy Pathways

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2475 ◽  
Author(s):  
You-Cheng Hseu ◽  
Ruei-Wan Lin ◽  
Yi-Chun Shen ◽  
Kai-Yuan Lin ◽  
Jiunn-Wang Liao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Dna Fragmentation ◽  
Caspase 3 ◽  
Parp Cleavage ◽  
Gastric Cancer Cells ◽  
Ags Cells ◽  
Induced Apoptosis

Chalcone flavokawain B (FKB) possesses a chemopreventive and anti-cancer activity. Doxorubicin is a chemotherapeutic DNA intercalating agent widely used in malignancy treatment. The present study investigated whether synergistic effects exist between the combination of FKB (1.25–5 µg/mL) and doxorubicin (0.5 µg/mL) on the apoptosis and autophagy in human gastric cancer (AGS) cells, and the possible in vitro and in vivo mechanisms. The MTT assay measured cell viability. Various apoptotic-, autophagy-associated protein expression was determined by the Western blot technique. FKB+doxorubicin synergy was estimated by the Chou-Talalay combination index (CI) method. In vivo studies were performed on BALB/c mice. Results showed that compared to FKB/doxorubicin treatments, low doses of FKB+doxorubicin suppressed AGS cell growth. FKB potentiated doxorubicin-induced DNA fragmentation, apoptotic cell death, and enhanced doxorubicin-mediated mitochondrial, death receptor pathways. FKB+doxorubicin activated increased LC3-II accumulation, p62/SQSTM1 expression, and AVO formation as compared to the FKB/doxorubicin alone treatments indicating autophagy in these cells. The death mechanism in FKB+doxorubicin-treated AGS cells is due to the activation of autophagy. FKB+doxorubicin-mediated dysregulated Bax/Bcl-2, Beclin-1/Bcl-2 ratios suggested apoptosis, autophagy induction in AGS cells. FKB+doxorubicin-induced LC3-II/AVOs downregulation was suppressed due to an apoptotic inhibitor Z-VAD-FMK. Whereas, 3-methyladenine/chloroquine weakened FKB+doxorubicin-induced apoptosis (decreased DNA fragmentation/caspase-3). Activation of ERK/JNK may be involved in FKB+doxorubicin-induced apoptosis and autophagy. FKB+doxorubicin-triggered ROS generation, but NAC attenuated FKB+doxorubicin-induced autophagic (LC3 accumulation) and apoptotic (caspase-3 activation and PARP cleavage) cell death. FKB+doxorubicin blocked gastric cancer cell xenografts in nude mice in vivo as compared to FKB/doxorubicin alone treatments. FKB and doxorubicin wielded synergistic anti-tumor effects in gastric cancer cells and is a promising therapeutic approach.

scholarly journals Arsenic trioxide induces apoptosis in human gastric cancer cells through up-regulation of p53 and activation of caspase-3

2001 ◽  
Vol 93 (6) ◽  
pp. 916-916 ◽  
Author(s):  
XH Jiang ◽  
BCY Wong ◽  
ST Yuen ◽  
SH Jiang ◽  
CH Cho ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Arsenic Trioxide ◽  
Caspase 3 ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells

Effect of trastuzumab on telomere-related proteins and the relationship to the sensitivity of HER2-amplified human gastric cancer cells to oxaliplatin and cisplatin.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 53-53
Author(s):  
Yongping Liu ◽  
Yang Ling ◽  
Qiu feng Qi ◽  
Yaodong Pan
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Annexin V ◽  
Human Gastric Cancer ◽  
Her2 Gene ◽  
Gastric Cancer Cells ◽  
Real Time Quantitative Pcr ◽  
Induced Apoptosis ◽  
Platinum Agents

53 Background: HER2 amplification occurs in about 20% of gastric cancers, and trastuzumab in combination with cisplatin based chemotherapy has been reported to improve oncological outcomes in gastric and gastro-oesophageal junction cancer with HER2 gene amplification. The aim of this study was to evaluate the potentially useful combined antitumor efficacy of trastuzumab and platinum agents in gastric cancer cells and to elucidate further the mechanisms possibly involved in the interaction between the trastuzumab and platinum agents. Methods: Gene expression was determined by using real-time quantitative PCR in gastric cancer cell lines. The chemosensitivity of gastric cancer cells to platinum agents and the apoptotic effect of drugs in vitro were evaluated using cellTiter 96 Aqueous One Solution Cell Proliferation Assay kit and double staining with both Annexin-V-FITC and PI, respectively. Results: Treatment with 1.0μg/ml trastuzumab for 48h could significantly increase sensitivity of oxaliplatin or cisplatin in HER2 amplified gastric cancer cells, and the IC50 of oxaliplatin and cisplatin were reduced to about 3.29 times and 6.91 times, respectively. Apoptosis analysis also indicated that trastuzumab significantly increased both oxaliplatin and cisplatin-induced apoptosis in NCI-N87 cells. Analysis of telomere-related genes revealed that trastuzumab singly and pretreatment with trastuzumab for 48h followed by oxaliplatin or cisplatin for another 48h could significantly downregulate the mRNA expression of TPP1, TRF1, TRF2, TRF2IP, POT1 and TIN2 genes. Conclusions: Our results describe the potential role of low dose trastuzumab to increase sensitivity of oxaliplatin and cisplatin in HER2 amplified gastric cancer cells, which may be partially through downregulating the expression levels of telomere-related genes.

scholarly journals Nicotine Inhibits Cisplatin-Induced Apoptosis via Regulating α5-nAChR/AKT Signaling in Human Gastric Cancer Cells

PLoS ONE ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. e0149120 ◽  
Author(s):  
Yanfei Jia ◽  
Haiji Sun ◽  
Hongqiao Wu ◽  
Huilin Zhang ◽  
Xiuping Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Akt Signaling ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Induced Apoptosis

Polyamine synthesis enzyme AMD1 is closely associated with tumorigenesis and prognosis of human gastric cancers

2019 ◽  
Vol 41 (2) ◽  
pp. 214-222 ◽  
Author(s):  
Lijiao Xu ◽  
Xue You ◽  
Qianqian Cao ◽  
Meiqin Huang ◽  
Lian-Lian Hong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Expression Level ◽  
Tumor Xenograft ◽  
Blood Vessel Invasion ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Gastric Cancers ◽  
Normal Tissues

Abstract Adenosylmethionine decarboxylase 1 (AMD1) is a key enzyme involved in biosynthesis of polyamines including spermidine and spermine. The potential function of AMD1 in human gastric cancers is unknown. We analyzed AMD1 expression level in 319 human gastric cancer samples together with the adjacent normal tissues. The protein expression level of AMD1 was significantly increased in human gastric cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The expression level of AMD1 was positively associated with Helicobactor pylori 16sRNA (P < 0.0001), tumor size (P < 0.0001), tumor differentiation (P < 0.05), tumor venous invasion (P < 0.0001), tumor lymphatic invasion (P < 0.0001), blood vessel invasion (P < 0.0001), and tumor lymph node metastasis (TNM) stage (P < 0.0001). Patients with high expression of AMD1 had a much shorter overall survival than those with normal/low expression of AMD1. Knockdown of AMD1 in human gastric cancer cells suppressed cell proliferation, colony formation and cell migration. In a tumor xenograft model, knockdown of AMD1 suppressed the tumor growth in vivo. Inhibition of AMD1 by an inhibitor SAM486A in human gastric cancer cells arrested cell cycle progression during G1-to-S transition. Collectively, our studies at the cellular, animal and human levels indicate that AMD1 has a tumorigenic effect on human gastric cancers and affect the prognosis of the patients.

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