Glutamate release inhibitor, Riluzole, inhibited proliferation of human hepatocellular carcinoma cells by elevated ROS production

Seol, Hyang Sook; Lee, Sang Eun; Song, Joon Seon; Lee, Hye Yong; Park, Sojung; Kim, Inki; Singh, Shree Ram; Chang, Suhwan; Jang, Se Jin

doi:10.1016/j.canlet.2016.08.028

Cited by 33 publications

(37 citation statements)

References 19 publications

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“…The cytochrome c in the cytoplasm then binds to Apaf-1 and further activates caspase-9. With the activation of caspase-9, caspase-3 is then active downstream, which results in the cleavage of various key cellular substrates, including PARP, resulting in the fragmentation of DNA and thus inducing cell apoptosis [33, 35]. …”

Section: Discussionmentioning

confidence: 99%

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Dai

Zheng

Guo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteosarcoma is a common primary malignant bone tumor that mainly occurs in childhood and adolescence. Despite developments in the diagnosis and treatment of osteosarcoma, the prognosis is still very poor. Cinobufagin is an active component in the anti-tumor Chinese medicine called “Chan Su”, and we previously revealed that cinobufagin induced apoptosis and reduced the viability of osteosarcoma cells; however, the underlying mechanism remains to be elucidated. Herein, the present study was undertaken to illuminate the molecular mechanism of cinobufagin-induced apoptosis of osteosarcoma cell. Methods: U2OS and 143B cells were treated with different concentrations of cinobufagin. Cell viability, colony formation ability and morphological changes were assessed by a CCK-8 assay, a clonogenic assay and light microscopy, respectively. Cell apoptosis was detected by Hoechst 33258 and Annexin V-FITC/PI staining. Reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were determined by flow cytometry. Glutathione (GSH) levels were detected by a GSH and GSSG assay kit. The levels of apoptosis-related proteins were determined by western blotting, and 143B cells were introduced to establish a xenograft tumor model. The effect of cinobufagin on osteosarcoma was further investigated in vivo. Results: Our results showed that cinobufagin significantly reduced the viability of U2OS and 143B cells in vitro in a dose-and time-dependent manner. In addition, cinobufagin-induced apoptosis in U2OS and 143B cells was concentration-dependent. Moreover, we found that cinobufagin treatment increased the level of intracellular ROS, decreased ΔΨm, reduced GSH and inhibited GSH reductase (GR). The effects of cinobufagin on cell proliferation, apoptosis, ROS generation and ΔΨm loss were dramatically reversed when the cells were pretreated with the thiol-antioxidants NAC or GSH. Moreover, cinobufagin treatment increased the expression of the pro-apoptotic protein Bax and decreased the expression of the anti-apoptitic protein Bcl-2, thus altering the ratio of Bax to Bcl-2. Furthermore, Cinobufagin treatment caused cytochrome c release from the mitochondria to cytoplasm, thus increasing the protein levels of cleaved-caspase family members to induce apoptosis. Ac-DEVD-CHO or Z-LEHD-FMK significantly reduced cinobufagin-induced apoptosis. Finally, a subcutaneous xenograft animal study verified that cinobufagin also significantly suppressed osteosarcoma growth in vivo. Conclusions: Our present data demonstrated that cinobufagin triggered cell apoptosis in osteosarcoma cells via the intrinsic mitochondria-dependent apoptosis pathway by the accumulation of ROS and the loss of ΔΨm. In an in vivo subcutaneous xenograft model, cinobufagin exhibited excellent tumor inhibitory effects. These results suggest that cinobufagin might potentially be further developed as an anti-tumor candidate for treating osteosarcoma patients in the clinic.

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Section: Discussionmentioning

confidence: 99%

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Dai

Zheng

Guo

et al. 2018

Cell Physiol Biochem

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“…International Publisher response of cancer to different anti-tumor treatments, including chemotherapy and radiotherapy [13][14][15][16].…”

Section: Ivyspringmentioning

confidence: 99%

Riluzole Enhances the Response of Human Nasopharyngeal Carcinoma Cells to Ionizing Radiation via ATM/P53 Signalling Pathway

Sun

Jun

et al. 2020

J. Cancer

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Riluzole is approved by the FDA as an amyotrophic lateral sclerosis (ALS) drug. Previous studies showed that treatment with riluzole suppressed the proliferation of many cancer cells. However, little is known about its effects on nasopharyngeal carcinoma (NPC) and its molecular mode of action. In this study, we determined the effect of riluzole on apoptosis, cell cycle, migration, and invasion in NPC cell lines and investigated its mechanism at the molecular level. By using the human NPC cell lines CNE1, CNE2, and HNE1, we revealed that riluzole effectively inhibited viability of the NPC cell lines in dose-and time-dependent manners. Furthermore, riluzole dose-dependently induced apoptosis and G2/M cell cycle arrest in the NPC cell lines. After combination with radiotherapy (RT), greater cytotoxicity was achieved than with riluzole or RT alone in vitro and vivo. This was associated with the activation of ataxia telangiectasia mutated (ATM) and phosphoinositide p53 pathways. P53 silencing reduced cell reactiveness to riluzole therapy. These observations demonstrate that the riluzole-activated ATM/P53 pathway is directly involved in radiation-induced apoptosis of NPC cells. Given the acceptable side effect, combining of riluzole and radiotherapy is promising in NPC treatment.

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“…It’s necessary to mention drugs that have been studied in vitro and in vivo with promising results, awaiting for trials on humans. Some examples are ursolic acid derivates[ 101 ] and a B5G9[ 102 ] (piperazidine derivative of 23-hydroxy betulinic acid), that cause ROS-mediated apoptosis in HCC cells, EMMQ[ 103 ] (an indolylquinoline derivative), that causes DNA damage by activating p53 and γ-H2AX, and GL63[ 104 ] (a curcumine analogue), which was able to suppress the proliferation of HCC cells by inhibition of the JAK2/STAT3 signaling pathway. Even Valproic Acid[ 105 ], a well-known antiepileptic drug, showed potential anti-HCC effect in vitro by promotion of epithelial mesenchymal transition of hepatocarcinoma cells via transcriptional and post-transcriptional up regulation of Snail.…”

Section: Future Perspectivesmentioning

confidence: 99%

Chemotherapy for hepatocellular carcinoma: The present and the future

Grazie¹,

Biagini²,

Tarocchi³

et al. 2017

WJH

156

137

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Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it’s still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatin- and gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

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Glutamate release inhibitor, Riluzole, inhibited proliferation of human hepatocellular carcinoma cells by elevated ROS production

Cited by 33 publications

References 19 publications

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Riluzole Enhances the Response of Human Nasopharyngeal Carcinoma Cells to Ionizing Radiation via ATM/P53 Signalling Pathway

Chemotherapy for hepatocellular carcinoma: The present and the future

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