scholarly journals Co-Treatment with the Epigenetic Drug, 3-Deazaneplanocin A (DZNep) and Cisplatin after DZNep Priming Enhances the Response to Platinum-Based Therapy in Chondrosarcomas

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4648
Author(s):  
Eva Lhuissier ◽  
Juliette Aury-Landas ◽  
Marion Lenté ◽  
Karim Boumediene ◽  
Catherine Baugé

Background: We have previously shown that 3-Deazaneplanocin A (DZNep) induces apoptosis in chondrosarcomas. Herein, we tested whether the combination of this epigenetic drug to a standard anticancer therapy may enhance the response to each drug in these bone tumors. Methods: Two chondrosarcoma cell lines (SW1353 and JJ012) were cultured in the presence of DZNep and/or cisplatin. Cell growth was evaluated by counting viable cells, and apoptosis was determined by Apo2.7 expression by flow cytometry. In vivo, the antitumoral effect of the DZNep/cisplatin combination was assessed through measurements of tumor volume of JJ012 xenografts in nude mice. Results: In vitro, the DZNep/cisplatin combination reduced cell survival and increased apoptosis compared to each drug alone in chondrosarcomas, but not in normal cells (chondrocytes). This enhancement of the antitumoral effect of the DZNep/cisplatin combination required a priming incubation with DZNep before the co-treatment with DZNep/cisplatin. Furthermore, in the chondrosarcoma xenograft mice model, the combination of both drugs more strongly reduced tumor growth and induced more apoptosis in tumoral cells than each of the drugs alone. Conclusion: Our results show that DZNep exposure can presensitize chondrosarcoma cells to a standard anticancer drug, emphasizing the promising clinical utilities of epigenetic-chemotherapeutic drug combinations in the future treatment of chondrosarcomas.

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1268 ◽  
Author(s):  
Kuan-Lin Kuo ◽  
Shing-Hwa Liu ◽  
Wei-Chou Lin ◽  
Po-Ming Chow ◽  
Yu-Wei Chang ◽  
...  

After chemotherapy for the treatment of metastatic bladder urothelial carcinoma (UC), most patients inevitably encounter drug resistance and resultant treatment failure. Deubiquitinating enzymes (DUBs) remove ubiquitin from target proteins and play a critical role in maintaining protein homeostasis. This study investigated the antitumor effect of PR-619, a DUBs inhibitor, in combination with cisplatin, for bladder UC treatment. Our results showed that PR-619 effectively induced dose- and time-dependent cytotoxicity, apoptosis, and ER-stress related apoptosis in human UC (T24 and BFTC-905) cells. Additionally, co-treatment of PR-619 with cisplatin potentiated cisplatin-induced cytotoxicity in UC cells and was accompanied by the concurrent suppression of Bcl-2. We also proved that Bcl-2 overexpression is related to the chemo-resistant status in patients with metastatic UC by immunohistochemistry (IHC) staining. In a xenograft mice model, we confirmed that PR-619 enhanced the antitumor effect of cisplatin on cisplatin-naïve and cisplatin-resistant UCs. Our results demonstrated that PR-619 effectively enhanced the cisplatin-induced antitumor effect via concurrent suppression of the Bcl-2 level. These findings provide promising insight for developing a therapeutic strategy for UC treatment.


RSC Advances ◽  
2016 ◽  
Vol 6 (99) ◽  
pp. 96946-96962 ◽  
Author(s):  
C. Balachandran ◽  
K. Chennakesava Rao ◽  
Y. Arun ◽  
N. Emi ◽  
N. Yamamoto ◽  
...  

In vitro and in vivo anticancer activity of compound 3a was proved as a novel blocker of JAK2/STAT3 signaling pathway and exerts both anti-proliferative and apoptotic activities in HepG-2 cells with xenograft mice model.


2020 ◽  
Vol 6 (1) ◽  
pp. 301-307
Author(s):  
Prashad N

Neuroblastoma is a common tumor of the peripheral nervous system in children. Highly aggressive MYC-drivenneuroblastoma is defined by increased MYC and/or MYCN expression. HDAC8 overexpression is associated with advanced neuroblastoma. Previously, we have demonstrated that transient knockdown of both Myc and Hdac8 using siRNA significantly suppressed neuroblastoma cells proliferation compared to knockdown of either target in vitro. In this study, we further investigated whether combinational targeting Myc and Hdac8 in neuroblastoma xenograft mice model is consistent with our previous findings. Intratumoral treatment with siRNA-MYC and siRNA-HDAC8 reduced the levels of the target MYC protein by 64% and HDAC8 by 85%; in addition, we found that the average tumor growth was reduced by 80% compared to that of control tumors treated with NC-siRNA. Our results suggest the potential therapeutic effect of the combination of siRNA-MYC and siRNA-HDAC8 for neuroblastoma treatment.


2021 ◽  
Vol 20 ◽  
pp. 153303382199000
Author(s):  
Suoli Cheng ◽  
Jianping Zheng ◽  
Xueqin Liu ◽  
Jiandang Shi ◽  
Fan Gong ◽  
...  

Background: Osteosarcoma is the most leading primary malignancy of the bone in adolescents all over the world. Long non-coding RNA (lncRNA) 91 H has been reported to participated in multiple cancers. Meanwhile, lncRNA 91 H has been proved to be upregulated in osteosarcoma. However, the function of 91 H in osteosarcoma remains unclear. Methods: Gene and protein expressions in osteosarcoma cells were detected by qRT-PCR and western blot, respectively. Cell viability was tested by CCK-8 assay. Ki67 staining was used to measure cell proliferation. Cell apoptosis and cycle were assessed by flow cytometry. In addition, transwell assay was used to detect cell migration and invasion. Furthermore, Methylation-specific PCR (MSP) was performed to test the methylation of CDK4 promoter. Finally, xenograft mice model was established to explore the role of 91 H in osteosarcoma in vivo. Results: Knockdown of 91 H significantly inhibited the growth of osteosarcoma cells via inducing the cell apoptosis. In addition, 91 H siRNA notably suppressed the migration and invasion of osteosarcoma cells. Meanwhile, knockdown of 91 H inhibited the progression of osteosarcoma via inducing methylation of CDK4 promoter. Furthermore, 91 H knockdown obviously induced G1 arrest in osteosarcoma cells via inhibition of PCNA and Cyclin D1. Finally, knockdown of 91 H notably inhibited the tumor growth of osteosarcoma in vivo. Conclusion: knockdown of 91 H suppressed the tumorigenesis of osteosarcoma via inducing methylation of CDK4 promoter in vitro and in vivo. Thus, 91 H may serve as a new target for the treatment of osteosarcoma.


2020 ◽  
Vol 11 ◽  
Author(s):  
Livan Delgado-Roche ◽  
Kethia González ◽  
Fernando Mesta ◽  
Beatriz Couder ◽  
Zaira Tavarez ◽  
...  

Marine plants are important sources of pharmacologically active metabolites. The aim of the present work was to evaluate the cytotoxic and antitumor activity of a polyphenolic fraction obtained from Thalassia testudinum marine plant and thalassiolin B in human colorectal cancer cells. Human cancer cell lines, including HCT15, HCT116, SW260, and HT29 were treated with tested products for cytotoxicity evaluation by crystal violet assay. The potential proapoptotic effect of these natural products was assessed by flow cytometry in HCT15 cells at 48 h using Annexin V-FITC/propidium iodide. In addition, reactive oxygen species (ROS) generation was measured by fluorescence using DCFH-DA staining, and sulfhydryl concentration by spectrophotometry. The in vivo antitumor activity of the polyphenolic fraction (25 mg/kg) was evaluated in a xenograft model in nu/nu mice. In vivo proapoptotic effect was also evaluated by immunohistochemistry using anti-caspase 3 and anti-Bcl-2 antibodies. The results showed that tested products exert colorectal cancer cell cytotoxicity. Besides, the tested products induced a significant increase (p < 0.05) of intracellular ROS generation, and a depletion of sulfhydryl concentration in HCT15 cells. The polyphenolic fraction arrested tumor growth and induced apoptosis in the xenograft mice model. These results demonstrate the cytotoxic activity of T. testudinum metabolites associated, at least, with ROS overproduction and pro-apoptotic effects. Here we demonstrated for the first time the antitumor activity of a T. testudinum polar extract in a xenograft mice model. These results suggest the potential use of T. testudinum marine plant metabolites as adjuvant treatment in cancer therapy.


2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Zeng ◽  
Xianggui Yang ◽  
Li Yang ◽  
Wancheng Li ◽  
Yaxin Zheng

Abstract Background Thymosin β10 (TMSB10) has been reported to play a protumorigenic role in a majority of solid cancers. However, the existence of TMSB10 in immune microenvironment may contribute to the pathogenesis of lung adenocarcinoma has not been previously explored. Method TAMs-associated TMSB10 expression was evaluated by immunohistochemistry (IHC) in 184 lung adenocarcinomas. Xenograft mice model was established to investigate the effect of TMSB10 shRNA on TAMs phenotypes. The macrophages phenotype associated cytokines IL-6, IL-8, IL-12 and TNF-α were detected by ELISA after treated with TMSB10 shRNA or scramble. Furthermore, the target proteins were detected by immunoblotting. Results We found that high TAMs-associated TMSB10 expression was significantly correlated with the advanced TNM stage and T3/T4 tumor size. And high TAMs-associated TMSB10 expression was significantly correlated with poor overall and progression-free survival of lung adenocarcinoma, acting as an independent prognostic factor for lung adenocarcinoma. Furthermore, we investigated the biological functions of TMSB10 in macrophages in vivo and in vitro. TMSB10 knockdown dramatically reduced TAMs, THP-1 and RAW264.7 cell proliferation, and promoted macrophages phenotype conversion of M2 to M1, and TMSB10 knockdown reduced the levels of p-Akt (Sec473), p-mTOR (Sec2448) and p-p70S6K (Thr389) without effect on Akt, mTOR and p70S6K expression. Conclusions These results demonstrate that TAMs-associated TMSB10 promotes tumor growth through increasing TAMs M2 conversion and proliferation via PI3K/Akt signaling pathway, providing a promising tumor biomarker for predicting prognosis and a potential therapeutic target for lung adenocarcinoma.


2020 ◽  
Author(s):  
Jun Zeng ◽  
Li Yang ◽  
Yaxin Zheng

Abstract Background: Thymosin β10 (TMSB10) has been reported to play a protumorigenic role in a majority of solid cancers. However, the function of TMSB10 in immune microenvironment may contribute to the pathobiology of lung adenocarcinoma has not been previously explored.Method: TAMs-associated TMSB10 expression was evaluated by immunohistochemistry (IHC) of 184 lung adenocarcinomas. Xenograft mice model was established to investigate the effect of TMSB10 shRNA on TAMs. The macrophages phenotype associated cytokines IL-6, IL-8 and TNF-α were detected by ELISA. Furthermore, the target proteins were detected by immunoblot.Results: We found that high TAMs-associated TMSB10 expression was significantly correlated with the advanced TNM stage and T3/T4 tumor size. And high TAMs-associated TMSB10 expression was significantly correlated with poor overall and progression-free survival of lung adenocarcinoma, acted as an independent prognostic factor for lung adenocarcinoma. Furthermore, we investigated the biological functions of TMSB10 in macrophages in vivo and in vitro. TMSB10 knockdown dramatically reduced TAMs, THP-1 and RAW264.7 cell proliferation, and promoted macrophages conversion of M2 to M1, and TMSB10 knockdown reduced the levels of p-Akt (Sec473), p-mTOR (Sec2448) and p-p70S6K (Thr389) without effect on Akt, mTOR and p70S6K expression.Conclusions: These results demonstrate that TAMs-associated TMSB10 promotes tumor growth through increasing TAMs M2 conversion and proliferation via PI3K/Akt signaling pathway, providing a promising tumor biomarker for predicting prognosis and a potential therapeutic target for lung adenocarcinoma.


2013 ◽  
Vol 14 (1) ◽  
pp. 409-412 ◽  
Author(s):  
Hai-Tao Yin ◽  
De-Geng Zhang ◽  
Xiao-Li Wu ◽  
Xin-En Huang ◽  
Gang Chen

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