Dioscin inhibits the growth of human osteosarcoma by inducing G2/M‐phase arrest, apoptosis, and GSDME‐dependent cell death in vitro and in vivo

2019 ◽  
Vol 235 (3) ◽  
pp. 2911-2924 ◽  
Author(s):  
Qiuyue Ding ◽  
Wenda Zhang ◽  
Cheng Cheng ◽  
Fengbo Mo ◽  
Lei Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Human Osteosarcoma ◽  
Phase Arrest ◽  
M Phase ◽  
Dependent Cell

scholarly journals Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Chantal B. Lucini ◽  
Ralf J. Braun
Keyword(s):  
Cell Death ◽  
Oxygen Species ◽  
In Vivo Models ◽  
Dependent Cell ◽  
Cell Death Mechanisms ◽  
Sting Pathway ◽  
Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

scholarly journals Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells

2019 ◽  
Vol 20 (9) ◽  
pp. 2069 ◽  
Author(s):  
Dmytro Starenki ◽  
Nadiya Sosonkina ◽  
Seung-Keun Hong ◽  
Ricardo V. Lloyd ◽  
Jong-In Park
Keyword(s):  
Cell Death ◽  
Thyroid Carcinoma ◽  
Thyroid Tumor ◽  
Anaplastic Thyroid Carcinoma ◽  
Mitochondrial Activity ◽  
Phase Arrest ◽  
M Phase ◽  
A Cell ◽  
Mitochondrial Hsp70

We previously reported that upregulation of mortalin (HSPA9/GRP75), the mitochondrial HSP70 chaperone, facilitates tumor cell proliferation and survival in human medullary thyroid carcinoma (MTC), proposing mortalin as a novel therapeutic target for MTC. In this report, we show that mortalin is also upregulated in other thyroid tumor types, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and anaplastic thyroid carcinoma (ATC), and that mortalin depletion can effectively induce growth arrest and cell death in human PTC (TPC-1), FTC (FTC133), and ATC (8505C and C643) cells in culture. Intriguingly, mortalin depletion induced varied effects on cell cycle arrest (G0/G1 phase arrest in TPC-1 and C643, G2/M phase arrest in 8505C, and mild G2/M phase arrest with increased sub-G0/G1 population in FTC133) and on the levels of TP53, E2F-1, p21CIP1, p27KIP1, and poly (ADP-ribose) polymerase cleavage in these cells, suggesting that thyroid tumor cells respond to mortalin depletion in a cell type-specific manner. In these cells, we also determined the efficacy of triphenyl-phosphonium-carboxy-proxyl (Mito-CP) because this mitochondria-targeted metabolism interfering agent exhibited similar tumor suppressive effects as mortalin depletion in MTC cells. Indeed, Mito-CP also induced robust caspase-dependent apoptosis in PTC and ATC cell lines in vitro, exhibiting IC50 lower than PLX4032 in 8505C cells and IC50 lower than vandetanib and cabozantinib in TPC-1 cells. Intriguingly, Mito-CP-induced cell death was partially rescued by mortalin overexpression, suggesting that Mito-CP may inactivate a mechanism that requires mortalin function. These findings support the significance of mortalin and mitochondrial activity in a broad spectrum of thyroid cancer.

Casticin Induced Apoptosis in A375.S2 Human Melanoma Cells through the Inhibition of NF-κB and Mitochondria-Dependent Pathways In Vitro and Inhibited Human Melanoma Xenografts in a Mouse Model In Vivo

2016 ◽  
Vol 44 (03) ◽  
pp. 637-661 ◽  
Author(s):  
Yin-Wen Shiue ◽  
Chi-Cheng Lu ◽  
Yu-Ping Hsiao ◽  
Ching-Lung Liao ◽  
Jing-Pin Lin ◽  
...  
Keyword(s):  
Human Melanoma ◽  
Oxygen Species ◽  
Protein Levels ◽  
Phase Arrest ◽  
Viable Cells ◽  
M Phase ◽  
Induced Apoptosis ◽  
Western Blotting Assay

Casticin, a polymethoxyflavone occurring in natural plants, has been shown to have anticancer activities. In the present study, we aims to investigate the anti-skin cancer activity of casticin on melanoma cells in vitro and the antitumor effect of casticin on human melanoma xenografts in nu/nu mice in vivo. A flow cytometric assay was performed to detect expression of viable cells, cell cycles, reactive oxygen species production, levels of [Formula: see text] and caspase activity. A Western blotting assay and confocal laser microscope examination were performed to detect expression of protein levels. In the in vitro studies, we found that casticin induced morphological cell changes and DNA condensation and damage, decreased the total viable cells, and induced G2/M phase arrest. Casticin promoted reactive oxygen species (ROS) production, decreased the level of [Formula: see text], and promoted caspase-3 activities in A375.S2 cells. The induced G2/M phase arrest indicated by the Western blotting assay showed that casticin promoted the expression of p53, p21 and CHK-1 proteins and inhibited the protein levels of Cdc25c, CDK-1, Cyclin A and B. The casticin-induced apoptosis indicated that casticin promoted pro-apoptotic proteins but inhibited anti-apoptotic proteins. These findings also were confirmed by the fact that casticin promoted the release of AIF and Endo G from mitochondria to cytosol. An electrophoretic mobility shift assay (EMSA) assay showed that casticin inhibited the NF-[Formula: see text]B binding DNA and that these effects were time-dependent. In the in vivo studies, results from immuno-deficient nu/nu mice bearing the A375.S2 tumor xenograft indicated that casticin significantly suppressed tumor growth based on tumor size and weight decreases. Early G2/M arrest and mitochondria-dependent signaling contributed to the apoptotic A375.S2 cell demise induced by casticin. In in vivo experiments, A375.S2 also efficaciously suppressed tumor volume in a xenotransplantation model. Therefore, casticin might be a potential therapeutic agent for the treatment of skin cancer in the future.

The Anti-Kappa Monoclonal Antibody MDX-1097 Synergizes with Immunomodulatory Drugs to Enhance Antibody-Dependent Cell Cytotoxicity of Multiple Myeloma Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4012-4012
Author(s):  
Andrew R Cuddihy ◽  
Parisa Asvadi ◽  
Rosanne Dunn ◽  
Tiffany T. Khong ◽  
Andrew Spencer
Keyword(s):  
Cell Death ◽  
Plasma Cells ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Immune Effector ◽  
Effector Cells ◽  
Dependent Cell ◽  
In Vitro Treatment

Abstract Abstract 4012 Multiple Myeloma (MM) is a cancer caused by the proliferation of malignant clonal plasma cells in the bone marrow and accounts for 10% of all hematologic malignancies. Recent advances have been made in the treatment and management of MM, however, despite these advances the majority of patients will ultimately relapse and die from their disease within 3–5 years from diagnosis. Several novel therapeutic approaches, including the use of antibody-based therapies, are being investigated to further improve the treatment of MM. MDX-1097 is a chimeric monoclonal antibody being assessed as a single agent in a Phase 2 clinical trial for the treatment of kappa light-chain restricted (κ-type) MM. MDX-1097 binds to the kappa myeloma antigen (KMA), a tumor-specific membrane-associated protein expressed on malignant plasma cells from patients with K-type MM. Previously we have demonstrated that MDX-1097 exerts its anti-tumour effects through multiple mechanisms, including antibody-dependent cell cytotoxicity (ADCC) in the presence of either normal human peripheral blood mononuclear cells (PBMCs) or purified natural killer (NK cells). The immunomodulatory drugs (IMiDs) lenalidomide (Revlimid) and pomalidomide (Actimid) are currently in use or being assessed for the treatment of MM. These IMiDs have been shown to exert their anti-tumor effects both directly, via apoptotic mechanisms, and indirectly via a number of different mechanisms including the augmentation of NK-dependent cellular cytotoxicity. In this study we report that IMiDs and MDX-1097 co-operate to promote enhanced ADCC of MM cells. In vitro treatment of normal PBMCs with IMiDs led to a 1.4-fold higher level of ADCC-mediated cell death of MDX-1097 spiked JJN3 cells (a κ-type MM cell line) compared with vehicle-treated PBMCs from the same donor. Similarly, in vivo lenalidomide exposed PBMCs isolated from a MM patient were, on average, 1.8-fold more effective in killing MDX-1097 spiked JJN3 cells in vitro compared to PBMC obtained from the same patient prior to lenalidomide treatment. Treatment of JJN3 cells with IMiDs resulted in significantly increased cell surface expression of KMA (lenalidomide: 1.9-fold, p < 0.001; pomalidomide: 2.3-fold, p < 0.01). These IMiD-treated JJN3 cells, when spiked with MDX-1097 were 1.7-fold more susceptible to ADCC-mediated cell death in the presence of untreated PBMCs, compared to JJN3 cells treated with vehicle alone. This difference in sensitivity to ADCC mediated cell death is presumably due to increased KMA expression resulting in more binding sites for MDX-1097, therefore facilitating recruitment of PB immune effector cells. Furthermore, combining IMiD-treated PBMCs with IMiD-treated, MDX-1097 spiked JJN3 cells resulted in a further increment in ADCC-mediated JJN3 cell death. This study demonstrates that in vivo and in vitro treatment of PBMCs with IMiDs engages the PB immune effector cells, leading to increased ADCC-induced κ-type MM cell death in vitro in the presence of MDX-1097. IMiDs also increase cell surface expression of KMA, leading to increased MDX-1097 binding and in turn also enhancing ADCC-induced MM cell killing. Our data provides a rationale for the clinical evaluation of a combination therapy involving both IMiDs and MDX-1097 for the treatment of k-type MM. Disclosures: Cuddihy: Immune System Therapeutics Ltd: Research Funding. Asvadi:Immune System Therapeutics Ltd: Employment. Dunn:Immune System Therapeutics Ltd: Employment, Equity Ownership. Spencer:Immune System Therapeutics Ltd: Research Funding.

scholarly journals Romidepsin Induces G2/M Phase Arrest and Apoptosis in Cholangiocarcinoma Cells

2020 ◽  
Vol 19 ◽  
pp. 153303382096075
Author(s):  
Pihong Li ◽  
Luguang Liu ◽  
Xiangguo Dang ◽  
Xingsong Tian
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Antitumor Effect ◽  
Caspase 3 ◽  
M Cell ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
M Phase

Background: Cholangiocarcinoma (CCA) is an extremely intractable malignancy since most patients are already in an advanced stage when firstly discovered. CCA needs more effective treatment, especially for advanced cases. Our study aimed to evaluate the effect of romidepsin on CCA cells in vitro and in vivo and explore the underlying mechanisms. Methods: The antitumor effect was determined by cell viability, cell cycle and apoptosis assays. A CCK-8 assay was performed to measure the cytotoxicity of romidepsin on CCA cells, and flow cytometry was used to evaluate the effects of romidepsin on the cell cycle and apoptosis. Moreover, the in vivo effects of romidepsin were measured in a CCA xenograft model. Results: Romidepsin could reduce the viability of CCA cells and induce G2/M cell cycle arrest and apoptosis, indicating that romidepsin has a significant antitumor effect on CCA cells in vitro. Mechanistically, the antitumor effect of romidepsin on the CCA cell lines was mediated by the induction of G2/M cell cycle arrest and promotion of cell apoptosis. The G2/M phase arrest of the CCA cells was associated with the downregulation of cyclinB and upregulation of the p-cdc2 protein, resulting in cell cycle arrest. The apoptosis of the CCA cells induced by romidepsin was attributed to the activation of caspase-3. Furthermore, romidepsin significantly inhibited the growth of the tumor volume of the CCLP-1 xenograft, indicating that romidepsin significantly inhibited the proliferation of CCA cells in vivo. Conclusions: Romidepsin suppressed the proliferation of CCA cells by inducing cell cycle arrest through cdc2/cyclinB and cell apoptosis by targeting caspase-3/PARP both in vitro and in vivo, indicating that romidepsin is a potential therapeutic agent for CCA.

scholarly journals Timosaponin AIII Induces G2/M Arrest and Apoptosis in Breast Cancer by Activating the ATM/Chk2 and p38 MAPK Signaling Pathways

2021 ◽  
Vol 11 ◽  
Author(s):  
Minjie Zhang ◽  
Jiaxi Qu ◽  
Zhiwei Gao ◽  
Qi Qi ◽  
Hong Yin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Mapk Pathways ◽  
Phase Arrest ◽  
M Phase ◽  
Timosaponin Aiii

Timosaponin AIII (TAIII), a steroidal saponin, exerts potent anti-tumor activity in various cancers, especially breast cancer. However, the concrete molecular mechanisms of TAIII against breast cancer are still unclear. Here, we find that TAIII triggers DNA damage, leads to G2/M arrest, and ultimately induces apoptosis in breast cancer both in vitro and in vivo. TAIII induced G2/M phase arrest and apoptosis in MDA-MB-231 and MCF7 cells accompanied with down-regulation of CyclinB1, Cdc2 and Cdc25C. Further data showed that the ATM/Chk2 and p38 pathways were activated representing by up-regulated levels of p-H2A.X and p-p38, which indicated an induction of DNA damage by TAIII, leading to cell cycle arrest and apoptosis. The effects of TAIII were further confirmed by employing inhibitors of ATM and p38 pathways. In vivo, TAIII suppressed the growth of subcutaneous xenograft tumor without obvious toxicity, which indicated by Ki67 and TUNEL analysis. Data also showed that TAIII stimulated the ATM/Chk2 and p38 MAPK pathways in vivo, which in consistent with the effects in vitro. Hence, our data demonstrate that TAIII triggers DNA damage and activates ATM/Chk2 and p38 MAPK pathways, and then induces G2/M phase arrest and apoptosis in breast cancer, which provide theoretical evidence for TAIII utilized as drug against breast cancer.

scholarly journals Imperatorin induces autophagy and G0/G1 phase arrest via PTEN-PI3K-AKT-mTOR/p21 signaling pathway in human osteosarcoma cells in vitro and in vivo

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Minchao Lv ◽  
Qingxin Xu ◽  
Bei Zhang ◽  
Zhiqiang Yang ◽  
Jun Xie ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Bioinformatic Analysis ◽  
Osteosarcoma Cells ◽  
Human Osteosarcoma ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
Human Osteosarcoma Cells ◽  
G1 Phase Arrest

Abstract Background Osteosarcoma is the third most common cancer in adolescence and the first common primary malignant tumor of bone. The long-term prognosis of osteosarcoma still remains unsatisfactory in the past decades. Therefore, development of novel therapeutic agents which are effective to osteosarcoma and are safe to normal tissue simultaneously is quite essential and urgent. Methods Firstly, MTT assay, cell colony formation assay, cell migration and invasion assays were conducted to evaluate the inhibitory effects of imperatorin towards human osteosarcoma cells. RNA-sequence assay and bioinformatic analysis were then performed to filtrate and assume the potential imperatorin-induced cell death route and signaling pathway. Moreover, quantitative real-time PCR assay, western blot assay and rescue experiments were conducted to confirm the assumptions of bioinformatic analysis. Finally, a subcutaneous tumor-transplanted nude mouse model was established and applied to evaluate the internal effect of imperatorin on osteosarcoma by HE and immunohistochemistry staining. Results Imperatorin triggered time-dependent and dose-dependent inhibition of tumor growth mainly by inducing autophagy promotion and G0/G1 phase arrest in vitro and in vivo. Besides, imperatorin treatment elevated the expression level of PTEN and p21, down-regulated the phosphorylation of AKT and mTOR. In contrast, the inhibition of PTEN using Bpv (HOpic), a potential and selective inhibitor of PTEN, concurrently rescued imperatorin-induced autophagy promotion, cell cycle arrest and inactivation of PTEN-PI3K-AKT-mTOR/p21 pathway. Conclusions This work firstly revealed that imperatorin induced autophagy and cell cycle arrest through PTEN-PI3K-AKT-mTOR/p21 signaling pathway by targeting and up-regulating PTEN in human osteosarcoma cells. Hence, imperatorin is a desirable candidate for clinical treatments of osteosarcoma.

HIF-1α-Mediated Mitophagy Determines ZnO Nanoparticle-Induced Human Osteosarcoma Cell Death both In Vitro and In Vivo

2020 ◽  
Vol 12 (43) ◽  
pp. 48296-48309
Author(s):  
Guanping He ◽  
Xiaoyu Pan ◽  
Xiao Liu ◽  
Ye Zhu ◽  
Yunlong Ma ◽  
...  
Keyword(s):  
Cell Death ◽  
Osteosarcoma Cell ◽  
Zno Nanoparticle ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cell
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