scholarly journals Ferritinophagy-Mediated ROS Production Contributed to Proliferation Inhibition, Apoptosis, and Ferroptosis Induction in Action of Mechanism of 2-Pyridylhydrazone Dithiocarbamate Acetate

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Longlong Li ◽  
Hao Li ◽  
Yongli Li ◽  
Jiankang Feng ◽  
Deng Guan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Biological Effects ◽  
Underlying Mechanism ◽  
Mechanistic Study ◽  
Ros Production ◽  
Nuclear Receptor Coactivator ◽  
Cellular Events ◽  
Cycle Arrest ◽  
Underlying Mechanisms

Reactive oxygen species (ROS) production is involved in the mechanism of action of a number of drugs, but the biological effects of ROS remain to be clarified. Furthermore, ferroptosis involves iron-dependent ROS production that may be derived from ferritinophagy; however, the association between ferroptosis and ferritinophagy has not been fully established. The present study demonstrated that dithiocarbamate derivatives (iron chelators) exhibited antineoplastic properties involving ferritinophagy induction, but whether the underlying mechanisms involved ferroptosis was unknown. To gain insight into the underlying mechanism, a dithiocarbamate derivative, 2-pyridylhydrazone dithiocarbamate s-acetic acid (PdtaA), was prepared. An MTT assay demonstrated that PdtaA inhibited proliferation involving ROS production ( I C 50 = 23.0 ± 1.5  μM for HepG2 cells). A preliminary mechanistic study revealed that PdtaA induced both apoptosis and cell cycle arrest. Notably, PdtaA also induced ferroptosis via downregulation of GPx4 and xCT, which was first reported for a dithiocarbamate derivative. Moreover, these cellular events were associated with ROS production. To explore the origin of ROS, expression of the ferritinophagy-related genes, ferritin, and nuclear receptor coactivator (NCOA4) were measured. Immunofluorescence and western blotting analysis indicated that PdtaA-induced ferritinophagy may contribute to ROS production. To investigate the role of ferritinophagy, autophagy inhibitor 3-methyladenin or genetic knockdown of NCOA4 was employed to inhibit ferritinophagy, which significantly neutralized the action of PdtaA in both apoptosis and ferroptosis. Taken together, PdtaA-induced cell cycle arrest, apoptosis, and ferroptosis were associated with ferritinophagy.

scholarly journals Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1453
Author(s):  
Haoran Wang ◽  
Jianhua Wei ◽  
Hong Jiang ◽  
Ye Zhang ◽  
Caina Jiang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Antitumor Agents ◽  
Mechanistic Study ◽  
Ros Generation ◽  
Polypyridyl Complexes ◽  
Expression Levels ◽  
Cycle Arrest ◽  
Study Results

The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (6a–6c) were synthesized as antitumor agents. Compounds 6a and 6c exhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly, 6a effectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of 6a and 6c, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that 6a and 6c arrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition, 6a and 6c caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca2+ release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that 6a and 6c exerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.

SMBA1, a Bax Activator, Induces Cell Cycle Arrest and Apoptosis in Malignant Glioma Cells

Pharmacology ◽  
2019 ◽  
Vol 105 (3-4) ◽  
pp. 164-172
Author(s):  
Shuangbo Fan ◽  
Qian Xu ◽  
Liang Wang ◽  
Yulin Wan ◽  
Sheng Qiu
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Biological Effects ◽  
Cyclin B1 ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
Cycle Arrest ◽  
Intrinsic Apoptosis Pathway ◽  
Induced Apoptosis ◽  
Dose Dependent

SMBA1 (small-molecule Bax agonists 1), a small molecular activator of Bax, is a potential anti-tumour agent. In the present study, we investigated the biological effects of SMBA1 on glioblastoma (GBM) cells. SMBA1 reduced the viabilities of U87MG, U251 and T98G cells in a time- and dose-dependent manner. Moreover, treatment with SMBA1 induced cell cycle arrest at the G2/M phase transition, accompanied by the downregulation of Cdc25c and cyclin B1 and the upregulation of p21. SMBA1 also induced apoptosis of GBM cells in a dose-dependent manner. Mechanistically, SMBA1 induced apoptosis via the intrinsic pathway. Silencing of Bax or ectopic expression of Bcl-2 significantly inhibited SMBA1-induced apoptosis. Moreover, SMBA1 inhibited the growth of U87MG xenograft tumours in vivo. Overall, SMBA1 shows anti-proliferative effects against GBM cells through activation of the intrinsic apoptosis pathway.

Wogonoside Exerts Anti-Leukemia of AML Cells Via Restricting Phospholipid Scramblase 1 Gene Expression and Promoting Its Translocation Into Nuclear

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4282-4282
Author(s):  
Yan Chen ◽  
Bao-An Chen ◽  
Qing-long Guo
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Underlying Mechanism ◽  
Phase Cell ◽  
Western Blots ◽  
Phospholipid Scramblase ◽  
Cycle Arrest ◽  
Phospholipid Scramblase 1

Abstract Abstract 4282 Objective: To evaluate the antileukemic effect of wogonoside and reveal the underlying mechanism. Method: In this study trypan blue dye exclusion assay, MTT assay, and soft agar colony formation assay were used to analysis growth inhibition of wogonoside the on AML (acute human promyelocytic) cell lines. Propidium iodide (PI)-staining and cell cycle-regulatory proteins detecting by western blots were applied to exam whether wogonoside could induce cell cycle arrest. Then a series of experiment were used to assess the ability of wogonoside to overcome the AML associated differentiation block, by using Giemsa staining, Nitroblue tetrazolium (NBT) reduction assay, and cell-surface differentiation antigens expression analysis. Real time PCR, western blots, cycloheximide inhibition test and RNA interference, nuclear and cytoplasmic fractionation, immunofluorescent staining were used to investigate the underlying mechanism. In this point we mainly focus that wogonoside exerts antileukemic by modulating of PLSCR1 gene expression, as well as influence its subcellular localization to play a role in regulating gene transcription. Result: It was demonstrated that wogonoside have the capacity to decrease the growth of myeloid cell lines by induction of G0/1 phase cell cycle arrest and differentiation. This effect is mediated by the increasing in mRNA and up-regulating protein expression of phospholipids scramblase 1 (PLSCR1). Meanwhile wogonoside promoted PLSCR1 traffic into the nucleus, which let PLSCR1 to play a role in regulating cell cycle and differentiation-related genes transcription including p21, p27, c-myc and IP3R1. Conclusion: Wogonoside induced AML cell lines to undergo differentiation and G1 phase arrest by restricting phospholipid scramblase 1 gene expression and promoting its translocation into nuclear. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The N-Terminal 24 Amino Acids of the p55 Gamma Regulatory Subunit of Phosphoinositide 3-Kinase Binds Rb and Induces Cell Cycle Arrest

2003 ◽  
Vol 23 (5) ◽  
pp. 1717-1725 ◽  
Author(s):  
Xianmin Xia ◽  
Aiwu Cheng ◽  
Damilola Akinmade ◽  
Anne W. Hamburger
Keyword(s):  
Cell Cycle ◽  
Amino Acid ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Cycle Progression ◽  
Regulatory Subunits ◽  
Cycle Arrest ◽  
Phosphoinositide 3 Kinase

ABSTRACT Although phosphoinositide 3-kinase (PI 3-kinase) is essential for cell cycle progression, the molecular mechanisms that regulate its diverse biological effects are poorly understood. We demonstrate here that Rb, a key regulator of cell cycle progression, associates with p55 kDa (p55α and p55γ) regulatory subunits of PI 3-kinase in vivo and in vitro. Both confocal microscopy and biochemical analysis demonstrated the presence of p55γ in the nucleus. The 24-amino-acid N-terminal end of p55γ, which is unique among PI 3-kinase regulatory subunits, was sufficient to bind Rb. Addition of serum or growth factors to quiescent cells triggered the dissociation of Rb from p55. Ectopic expression of the 24-amino-acid N-terminal end of p55γ inhibited cell cycle progression, as evidenced by induction of cell growth arrest at the G0/G1 phase, inhibition of DNA synthesis, inhibition of cyclin D and cyclin E promoter activity, and changes in the expression of cell cycle-related proteins. The inhibitory effects of the N-terminal end of p55γ on cell cycle progression depended on the presence of functional Rb. These data demonstrate for the first time an association of p55γ with Rb and show that modification of this association can lead to cell cycle arrest.

scholarly journals Pinocembrin flavanone inhibits cell viability in PC-3 human prostate cancer by inducing cellular apoptosis, ROS production and cell cycle arrest

2021 ◽  
Vol 71 (4) ◽  
pp. 669-678
Author(s):  
Linhai Shao ◽  
Yajun Shao ◽  
Yu Yuan
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Human Prostate ◽  
Ros Production ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Dose Dependent

Abstract The main purpose of the present study was to evaluate the antitumor effects of pinocembrin in human prostate cancer cells (PC-3) along with investigating its effects on cell apoptosis, endogenous ROS production and cell cycle. MTT assay and clonogenic assays were used to study the effects on cell viability and cancer colony formation, respectively. Fluorescence microscopy along with Western blotting was used to study apoptotic effects induced by pinocembrin. Flow cytometry was used to study effects on ROS production and cell cycle phase distribution. Results indicated that pinocembrin promoted inhibition cell proliferation along with reducing cancer colony formation of PC-3 cells in a dose-dependent manner. Pinocembrin induced regulatory effects over expressions of caspase-3, caspase-9, Bax and Bcl-2, thereby promoting apoptotic cell death in PC-3 cells. It also led to the dose-dependent G0/G1 cell cycle arrest. In conclusion, pinocembrin exhibits strong anticancer effects in human prostate cancer cells mediated via apoptosis, endogenous ROS production and G0/G1 cell cycle arrest.

scholarly journals Albanol B from Mulberries Exerts Anti-Cancer Effect through Mitochondria ROS Production in Lung Cancer Cells and Suppresses In Vivo Tumor Growth

2020 ◽  
Vol 21 (24) ◽  
pp. 9502
Author(s):  
Thanh Nam Phan ◽  
Okwha Kim ◽  
Manh Tuan Ha ◽  
Cheol Hwangbo ◽  
Byung-Sun Min ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cyclin B1 ◽  
Lung Cancer Cells ◽  
Ros Production ◽  
Cycle Arrest ◽  
Mitochondrial Ros ◽  
Anti Cancer

Albanol B (ABN-B), an arylbenzofuran derivative isolated from mulberries, has been shown to have anti-Alzheimer’s disease, anti-bacterial and antioxidant activities. The aim of this study was to investigate the anti-cancer effect of this compound against lung cancer cells. The results show that ABN-B inhibited the proliferation of four human lung cancer cell lines (A549, BZR, H1975, and H226) and induced apoptosis, based on the cleavage of caspase-7 and PARP (poly (ADP-ribose) polymerase), as well as the downregulation of Bcl-2. ABN-B also induced cell cycle arrest at G2/M by down-regulating the expression of CKD1 (cyclin-dependent kinase 1) and cyclin B1, but up-regulating p21 (cyclin-dependent kinase inhibitor 1) expression. Notably, ABN-B increased the production of mitochondrial reactive oxygen species (ROS); however, treatment with mito-TEMPO (a specific mitochondrial antioxidant) blocked ABN-B-induced cell cycle arrest at G2/M and apoptosis, as well as the up-regulation of p21 and down-regulation of CDK1 and cyclin B1 induced by ABN-B. At the molecular level, ABN-B-induced mitochondrial ROS production increased the phosphorylation levels of AKT (protein kinase B) and ERK1/2 (extracellular signal-regulated kinase 1/2), while the inhibition of these kinases blocked the ABN-B-induced up-regulation of p21 and down-regulation of CDK1 and cyclin B1. Moreover, ABN-B significantly suppressed tumor growth in Ex-3LL (Lewis lung carcinoma) tumor-bearing mice. Taken together, these results suggest that ABN-B can exert an anti-cancer effect by inducing apoptosis and cell cycle arrest at G2/M through mitochondrial ROS production in lung cancer cells.

Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule

Blood ◽  
2011 ◽  
Vol 118 (23) ◽  
pp. 6123-6131 ◽  
Author(s):  
Harald Ehrhardt ◽  
David Schrembs ◽  
Christian Moritz ◽  
Franziska Wachter ◽  
Subrata Haldar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Childhood Leukemia ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Vinca Alkaloids ◽  
Cycle Arrest ◽  
Induced Apoptosis

Abstract Application of anthracyclines and Vinca alkaloids on the same day represents a hallmark of polychemotherapy protocols for hematopoietic malignancies. Here we show, for the first time, that both drugs might act most efficiently if they are applied on different days. Proof-of-concept studies in 18 cell lines revealed that anthracyclines inhibited cell death by Vinca alkaloids in 83% of cell lines. Importantly, in a preclinical mouse model, doxorubicin reduced the anti–tumor effect of vincristine. Both drugs acted in a sequence-dependent manner and the strongest anti–tumor effect was obtained if both drugs were applied on different days. Most notably for clinical relevance, in 34% of 35 fresh primary childhood leukemia cells tested in vitro, doxorubicin reduced the anti–tumor effect of vincristine. As underlying mechanism, doxorubicin activated p53, p53 induced cell-cycle arrest, and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine; therefore, vincristine was unable to activate downstream apoptosis signaling. As molecular proof, antagonism was rescued by knockdown of p53, whereas knockdown of cyclin A inhibited vincristine-induced apoptosis. Our data suggest evaluating anthracyclines and Vinca alkaloids on different days in future trials. Selecting drug combinations based on mechanistic understanding represents a novel conceptional strategy for potent polychemotherapy protocols.

scholarly journals Dose Dependent Biological Effects of Idarubicin in HL-60 Cells: Alterations of the Cell-Cycle and Apoptosis

2000 ◽  
Vol 43 (2) ◽  
pp. 69-73 ◽  
Author(s):  
Martina Mareková ◽  
Jiřina Vávrová ◽  
Doris Vokurková
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Low Dose ◽  
Biological Effects ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Cycle Arrest ◽  
Dose Dependent ◽  
Massive Apoptosis ◽  
Human Leukaemia

TP-53 deficient cells of human leukaemia HL-60 die by massive apoptosis after treatment by high (50-100 nmol/l) doses of DNA damaging agent Idarubicin, regardless of the cell-cycle phase, in which they are affected. In contrary, after relatively low dose 10 nmol/l the cells die after cell-cycle arrest in G2phase. The results show, that apoptosis induced by idarubicin could appear independently of the cell-cycle phase and that period in which apoptosis is observed is related to the dose of Idarubicin.

scholarly journals miR-422a inhibits osteosarcoma proliferation by targeting BCL2L2 and KRAS

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Hao Zhang ◽  
Qian-Yun He ◽  
Guang-Chao Wang ◽  
Da-Ke Tong ◽  
Ren-Kai Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Underlying Mechanism ◽  
Clinical Samples ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. However, the underlying mechanism of osteosarcoma carcinogenesis and progression remains unknown. In the present study, we evaluated the expression profile of miRNAs in osteosarcoma tissues and the adjacent normal tissues. We found that the expression of miR-422a was down-regulated in osteosarcoma tissues and cell lines. In addition, we observed significantly elevated levels of repressive H3K9me3 and H3K27me3 and decreased active H3K4me3 on the promote region of miR-422a in osteosarcoma cells and clinical samples. Furthermore, up-regulation of miR-422a exhibited both in vitro and in vivo anti-tumor effects by inhibiting osteosarcoma cell growth and inducing apoptosis and cell cycle arrest. We also found that miR-422a targeted BCL2L2 and KRAS and negatively regulated their protein expression. Furthermore, restoration of miR-422a and knockdown of BCL2L2 and KRAS promoted apoptosis and induce cell cycle arrest in osteosarcoma cells. Taken together, the present study demonstrates that miR-422a may serve as a tumor suppressor in osteosarcoma via inhibiting BCL2L2 and KRAS translation both in vitro and in vivo. Therefore, miR-422a could be developed as a novel therapeutic target in osteosarcoma.

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