scholarly journals Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Md Sazzad Hassan ◽  
Nicholas Cwidak ◽  
Chloe Johnson ◽  
Silvio Däster ◽  
Serenella Eppenberger-Castori ◽  
...  

Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21043-21043
Author(s):  
J. Y. Chang ◽  
R. Komaki ◽  
X. Zhang ◽  
L. Wang ◽  
B. Fang

21043 Background: Only 25% of esophageal cancer patients achieve pathological complete response after standard chemoradiotherapy. Radiation dose escalation is associated with higher toxicity but no therapeutic improvement. In addition, esophageal cancer cells may develop radiation resistance (RR) after fractionated radiation exposure. Therefore, molecular targeting therapy for RR esophageal cancer is urgently needed. Methods: Six pairs of RR esophageal cancer cell lines were established by applying continuous 2 Gy fractionated irradiation. Ad/TRAIL-E1, an oncolytic adenoviral vector expressing both apoptotic TRAIL and viral E1A genes under the control of tumor specific human telomerase reverse transcriptase promoter, was constructed. Phosphate buffer solution and vectors expressing the TRAIL gene only, the GFP marker protein only, or the E1A gene only served as controls. Trans-gene expression, apoptosis activation, and the RR esophageal cancer cells targeted were evaluated in vitro and in vivo. A human esophageal RR cancer model was established and locally treated with Ad/TRAIL-E1 or controls. Results: After fractionated radiation exposure, esophageal cancer cell lines developed RR (up to 25-fold) that was associated with activation of the anti-apoptotic pathway. Ad/TRAIL-E1 activated an apoptotic cascade of caspases and selectively killed esophageal cancer cells but not normal cells. Ad/TRAIL-E1 preferentially targeted RR stem-like cancer cells with higher trans-gene expression and cell killing compared with parental cells. Overexpression (3 times) of Coxsackie's and adenoviral receptors in RR esophageal cancer cells compared with parental cells was noted. Ad/TRAIL-E1 therapy resulted in 40% tumor-free survival without the treatment- related toxicity found in human RR esophageal adenocarcinoma mouse models (p<0.05 as compared with controls). Conclusions: Esophageal cancer cells develop RR after fractionated radiation exposure. Ad/TRAIL-E1 preferentially targeted RR stem-like esophageal cancer cells, which resulted in a 40% cure rate. No significant financial relationships to disclose.


Open Medicine ◽  
2016 ◽  
Vol 11 (1) ◽  
pp. 31-35 ◽  
Author(s):  
Lin Jingjing ◽  
Wang Wangyue ◽  
Xu Qiaoqiao ◽  
Ye Jietong

AbstractObjectivesIncreasing evidence showed that microRNAs (miRNAs) were implicated in the chemical resistance of human cancers. We intended to investigate the role of miR-218 in cisplatin sensitivity of esophageal cancer cells.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) was carried out to analyze miR-218 expression in human esophageal cancer cell line Eca9706 and a cisplatin-resistant subline (ECa9706-CisR cells). The effects of miR-218 transfection on ECa9706 and ECa9706-CisR cell viability, including cell viability and apoptosis rate were confirmed using MTT assay, or flow cytometry, respectively. qRT-PCR was used to validate survivin as a direct target gene of miR-218 in our system.ResultsWe found that miR-218 was significantly decreased in ECa9706-CisR cells compared with parent Eca9706 cells. Overexpression of miR-218 by mimics transfection would enhance cisplatin sensitivity evaluated by cell viability inhibition and apoptosis promotion. We validated here survivin as a direct target of miR-218 in ECa9706 cells, which might contribute to the chemoresistance of esophageal cancer cells to cisplatin.ConclusionsIn summary, our data suggest that miR-218 might represent as a promising sensitizer of cisplatin therapy in clinical esophageal cancer patients.


2015 ◽  
Vol 6 (7-8) ◽  
pp. 356-364 ◽  
Author(s):  
Ji Hee Ha ◽  
Rohini Gomathinayagam ◽  
Mingda Yan ◽  
Muralidharan Jayaraman ◽  
Rajagopal Ramesh ◽  
...  

Author(s):  
Bo Zuo ◽  
Na Wu ◽  
Shen Yang ◽  
Zhaohui Zhong ◽  
Mei Li ◽  
...  

Abstract Purpose G-protein coupled receptor (GPR 34) has been found to play important roles in some cancers and regulates the proliferation, apoptosis, and migration of these cancer cells. However, the mechanisms underlying how GPR34 functions to regulate growth and proliferation of colorectal cancer cells remains to be clarified. Methods We employed stable GPR34 knockdown LS174T cell models, GPR34 Mab blocking, a CCK-8 kit, and a colony formation assay to characterize the effect of GPR34 on the proliferation of LS174T in vitro and xenograft tumor growth in vivo. The mRNA level of GPR34 was detected by RT-PCR in tumor tissues and adjacent normal tissues from 34 CRC patients. Results Based on RT-PCR results, GPR34 exhibited high level in tumor samples compared with adjacent normal samples. Increased expression of GPR34 is more associated with poor prognosis of CRC as shown in The Cancer Genome Atlas (TCGA) dataset by Kaplan–Meier survival analysis. Furthermore, we showed that GPR34 knockdown inhibited the proliferation of LS174T colon cancer cells and related xenograft tumor growth. Searching for the distinct molecular mechanism, we identified several contributors to proliferation of LS174T colon cancer cells: PI3K subunits/PTEN, PDK1/AKT, and Src/Raf/Ras/ERK. GPR34 knockdown inhibited the proliferation of LS174T cells by upregulating expression of PTEN, and downregulating expression of PI3K subunits p110-beta. Conclusion Our findings provide direct evidence that GPR34 regulates the proliferation of LS174T cells and the growth of LS174T tumor xenografts by regulating different pathways. High expression of GPR34 mRNA could then be used to predict poor prognosis of CRC.


2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Cailing Jiang ◽  
Shumin Li ◽  
Yanjing Li ◽  
Yuxian Bai

Despite recent advances in chemotherapy and surgical resection, the 5-year survival rate of esophageal cancer still remains at the low level. Therefore, it is very important to discover a new agent to improve the life expectancy of patients with esophageal cancer. Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has recently exhibited promising anticancer activity against various cancer cells. But so far, the specific mechanism remains unclear. We have previously demonstrated that DHA reduced viability of esophageal cancer cells in a dose-dependent manner in vitro and induced cell cycle arrest and apoptosis. Here, we extended our study to further observe the efficacy of DHA on esophageal cancer cells in vivo. In the present study, for the first time, we found that DHA significantly inhibits cell proliferation in xenografted tumor compared with the control. The mechanism was that DHA induced cell apoptosis in both human esophageal cancer cell lines Eca109 and Ec9706 in vivo in a dose-dependent manner. The results suggested that DHA was a promising agent against esophageal cancer in the clinical treatment.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15501-e15501
Author(s):  
Jingping Yu

e15501 Background: To investigate the effects of apatinib on esophageal cancer cells in vitro and xenograft models, and discuss the mechanisms of its actions. Methods: Used various assays to measure the different biological processes of esophageal cancer cells: used MTT assay to measure the proliferation rate; used transwell assay to determine the migration capacity and used colony formation assay to assess the clone formation rate. The effect of apatinib on cell cycle and apoptosis was analyzed by flow cytometry. The expression levels of VEGF and VEGFR2 were measured by qRT-PCR. The concentration of VEGF in the supernatant of cancer cell was assessed by ELISA. The expression levels of MEK, ERK, p-MEK, p-ERK, STAT3, p-STAT3, CHK2 and CDC2 after VEGF stimulation were detected by western blot. We also established human esophageal squamous carcinoma xenograft model in nude mice. The mice were randomly divided into healthy control group, low dose group (250mg) and high dose group (500mg), with 6 mice in each group. The tumor growth rate of each group was calculated, and the expression levels of VEGF and VEGFR2 in tumor tissues were detected by immunohistochemistry. Results: Apatinib inhibited the proliferation of esophageal cancer cell in a time-dependent (P < 0.05) and concentration-dependent (P < 0.05) manner; it also inhibited the cell migration capacity (P < 0.05) and colony formation rate (P < 0. 05). In addition, apatinib induced apoptosis in esophageal cancer cells and increased the proportion of cells in G2 / M phase (P < 0.05). The mRNA levels of VEGF (P < 0.05) and VEGFR2 (P < 0.05) and the protein levels of VEGF (P < 0.05) were also suppressed by apatinib. Western blot showed that apatinib could down-regulate the expression of p-MEK, p-ERK, STAT3, p-STAT3, CHK2 and CDC2 (P < 0.05). The inhibition rates of apatinib in esophageal carcinoma xenograft model was 29.25% and 19.96% for 250mg and 500mg drug treatment groups. Compared with healthy control group, the VEGF levels in drug treatment groups were not significantly different (P > 0.05), but the VEGFR2 levels were significantly decreased (P < 0.05). Conclusions: Apatinib can induce apoptosis of esophageal cancer cell KYSE-150 and ECA-109, and inhibit the cell proliferation, migration and colony formation. Moreover, apatinib can inhibit the tumor growth in esophageal carcinoma xenograft models. This inhibitory action of apatinib is related to the alterations in VEGF-related pathways such as Ras / Raf / MEK / ERK and JAK2 / STAT3 pathways.


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