Pseudolaric Acid B Induces Caspase-Dependent and Caspase-Independent Apoptosis in U87 Glioblastoma Cells

Pseudolaric acid B (PLAB) is one of the major bioactive components ofPseudolarix kaempferi. It has been reported to exhibit inhibitory effect on cell proliferation in several types of cancer cells. However, there is no report elucidating its effect on glioma cells and organ toxicityin vivo. In the present study, we found that PLAB inhibited growth of U87 glioblastoma cells in a dose-dependent manner with IC50~10 μM. Flow cytometry analysis showed that apoptotic cell death mediated by PLAB was accompanied with cell cycle arrest at G2/M phase. Using Western blot, we found that PLAB induced G2/M phase arrest by inhibiting tubulin polymerization in U87 cells. Apoptotic cell death was only partially inhibited by pancaspase inhibitor, z-VAD-fmk, which suggested that PLAB-induced apoptosis in U87 cells is partially caspase-independent. Further mechanistic study demonstrated that PLAB induced caspase-dependent apoptosis via upregulation of p53, increased level of proapoptotic protein Bax, decreased level of antiapoptotic protein Bcl-2, release of cytochrome c from mitochondria, activation of caspase-3 and proteolytic cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-independent apoptosis through apoptosis inducing factor (AIF). Furthermore,in vivotoxicity study demonstrated that PLAB did not induce significant structural and biochemical changes in mouse liver and kidneys at a dose of 25 mg/kg. Therefore, PLAB may become a potential lead compound for future development of antiglioma therapy.

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Combination of Arsenic Trioxide and Valproic Acid Efficiently Inhibits Growth of Lung Cancer Cells via G2/M-Phase Arrest and Apoptotic Cell Death

International Journal of Molecular Sciences ◽

10.3390/ijms21072649 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2649

Author(s):

Hyun Kyung Park ◽

Bo Ram Han ◽

Woo Hyun Park

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Cancer Cells ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Lung Cancer Cells ◽

Phase Arrest ◽

Anti Cancer ◽

M Phase

Arsenic trioxide (ATO; As2O3) has anti-cancer effects in various solid tumors as well as hematological malignancy. Valproic acid (VPA), which is known to be a histone deacetylase inhibitor, has also anti-cancer properties in several cancer cells including lung cancer cells. Combined treatment of ATO and VPA (ATO/VPA) could synergistically enhance anti-cancer effects and reduce ATO toxicity ATO. In this study, the combined anti-cancer effects of ATO and VPA (ATO/VPA) was investigated in NCI-H460 and NCI-H1299 lung cancer cells in vitro and in vivo. A combination of 3 μM ATO and 3 mM VPA (ATO/VPA) strongly inhibited the growths of both lung cancer cell types. DNA flow cytometry indicated that ATO/VPA significantly induced G2/M-phase arrest in both cell lines. In addition, ATO/VPA strongly increased the percentages of sub-G1 cells and annexin V-FITC positive cells in both cells. However, lactate dehydrogenase (LDH) release from cells was not increased in ATO/VPA-treated cells. In addition, ATO/VPA increased apoptosis in both cell types, accompanied by loss of mitochondrial membrane potential (MMP, ∆Ψm), activation of caspases, and cleavage of anti-poly ADP ribose polymerase-1. Moreover, a pan-caspase inhibitor, Z-VAD, significantly reduced apoptotic cell death induced by ATO/VPA. In the xenograft model, ATO/VPA synergistically inhibited growth of NCI-H460-derived xenograft tumors. In conclusion, the combination of ATO/VPA effectively inhibited the growth of lung cancer cells through G2/M-phase arrest and apoptotic cell death, and had a synergistic antitumor effect in vivo.

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The novel synthesized 2-(3-(methylamino)phenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (Smh-3) compound induces G2/M phase arrest and mitochondrial-dependent apoptotic cell death through inhibition of CDK1 and AKT activity in HL-60 human leukemia cells

International Journal of Oncology ◽

10.3892/ijo.2011.952 ◽

2011 ◽

Vol 38 (5) ◽

Cited By ~ 5

Author(s):

Huang

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Leukemia Cells ◽

Human Leukemia ◽

The Novel ◽

Human Leukemia Cells ◽

Phase Arrest ◽

M Phase

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Nucleotide Biosynthesis Links Glutathione Metabolism to Ferroptosis Sensitivity

10.1101/2021.07.14.452394 ◽

2021 ◽

Author(s):

Amy Tarangelo ◽

Joon Tae Kim ◽

Jonathan Z Long ◽

Scott J Dixon

Keyword(s):

Cell Death ◽

De Novo ◽

Apoptotic Cell ◽

Lipid Peroxides ◽

Nucleotide Metabolism ◽

Apoptotic Cell Death ◽

Death Process ◽

Glutathione Metabolism ◽

Dependent Manner ◽

Nucleotide Synthesis

Nucleotide synthesis is a metabolically demanding process essential for cell division. Several anti-cancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we report that inhibition of nucleotide metabolism by the p53 pathway is sufficient to suppress the non-apoptotic cell death process of ferroptosis. Mechanistically, stabilization of wild-type p53 and induction of the p53 target gene CDKN1A (p21) leads to decreased expression of the ribonucleotide reductase (RNR) subunits RRM1 and RRM2. RNR is the rate-limiting enzyme of de novo nucleotide synthesis that reduces ribonucleotides to deoxyribonucleotides in a glutathione-dependent manner. Direct inhibition of RNR conserves glutathione which can then be used to limit the accumulation of toxic lipid peroxides, preventing the onset of ferroptosis. These results support a mechanism linking p53-dependent regulation of nucleotide metabolism to non-apoptotic cell death.

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Contribution of TNF-α to Leukocyte Adhesion, Vascular Leakage, and Apoptotic Cell Death in Endotoxin-Induced Uveitis In Vivo

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.02-0589 ◽

2003 ◽

Vol 44 (5) ◽

pp. 2184 ◽

Cited By ~ 91

Author(s):

Kan Koizumi ◽

Vassiliki Poulaki ◽

Sven Doehmen ◽

Gerhard Welsandt ◽

Sven Radetzky ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Leukocyte Adhesion ◽

Apoptotic Cell Death ◽

Vascular Leakage ◽

Tnf Α

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Shiga Toxins Activate the NLRP3 Inflammasome Pathway To Promote Both Production of the Proinflammatory Cytokine Interleukin-1β and Apoptotic Cell Death

Infection and Immunity ◽

10.1128/iai.01095-15 ◽

2015 ◽

Vol 84 (1) ◽

pp. 172-186 ◽

Cited By ~ 28

Author(s):

Moo-Seung Lee ◽

Haenaem Kwon ◽

Eun-Young Lee ◽

Dong-Jae Kim ◽

Jong-Hwan Park ◽

...

Keyword(s):

Cell Death ◽

Nlrp3 Inflammasome ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Interleukin 1Β ◽

Dependent Manner ◽

Shiga Toxins ◽

Caspase 1 ◽

Immune Signaling Pathway ◽

Tnf Α

Shiga toxin (Stx)-mediated immune responses, including the production of the proinflammatory cytokines tumor necrosis-α (TNF-α) and interleukin-1β (IL-1β), may exacerbate vascular damage and accelerate lethality. However, the immune signaling pathway activated in response to Stx is not well understood. Here, we demonstrate that enzymatically active Stx, which leads to ribotoxic stress, triggers NLRP3 inflammasome-dependent caspase-1 activation and IL-1β secretion in differentiated macrophage-like THP-1 (D-THP-1) cells. The treatment of cells with a chemical inhibitor of glycosphingolipid biosynthesis, which suppresses the expression of the Stx receptor globotriaosylceramide and subsequent endocytosis of the toxin, substantially blocked activation of the NLRP3 inflammasome and processing of caspase-1 and IL-1β. Processing and release of both caspase-1 and IL-1β were significantly reduced or abolished in Stx-intoxicated D-THP-1 cells in which the expression of NLRP3 or ASC was stably knocked down. Furthermore, Stx mediated the activation of caspases involved in apoptosis in an NLRP3- or ASC-dependent manner. In Stx-intoxicated cells, the NLRP3 inflammasome triggered the activation of caspase-8/3, leading to the initiation of apoptosis, in addition to caspase-1-dependent pyroptotic cell death. Taken together, these results suggest that Stxs trigger the NLRP3 inflammasome pathway to release proinflammatory IL-1β as well as to promote apoptotic cell death.

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O-GlcNAc Transferase Inhibitor Synergistically Enhances Doxorubicin-Induced Apoptosis in HepG2 Cells

Cancers ◽

10.3390/cancers12113154 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3154

Author(s):

Su Jin Lee ◽

Oh-Shin Kwon

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Hepg2 Cells ◽

Drug Targets ◽

Apoptotic Cell ◽

Chemotherapy Resistance ◽

Apoptotic Cell Death ◽

Induced Apoptosis ◽

Glcnac Transferase

The combination of chemotherapy with chemosensitizing agents is a common approach to enhance anticancer activity while reducing the dose-dependent adverse side effects of cancer treatment. Herein, we investigated doxorubicin (DOX) and O-GlcNAc transferase (OGT) inhibitor OSMI-1 combination treatment, which significantly enhanced apoptosis in hepatocellular carcinoma cells (HepG2) as a result of synergistic drug action in disparate stress signaling pathways. Treatment with a low dose of DOX or a suboptimal dose of OSMI-1 alone did not induce apoptotic cell death in HepG2 cells. However, the combination of DOX with OSMI-1 in HepG2 cells synergistically increased apoptotic cell death through the activation of both the p53 and mitochondrial Bcl2 pathways compared to DOX alone. We also demonstrated that the combination of DOX and OSMI-1 stimulated cell death, dramatically reducing cell proliferation and tumor growth in vivo using a HepG2 xenograft mouse model. These findings indicate that OSMI-1 acts as a potential chemosensitizer by enhancing DOX-induced cell death. This study provides insight into a possible mechanism of chemotherapy resistance, identifies potential novel drug targets, and suggests that OGT inhibition could be utilized in clinical applications to treat hepatocellular carcinoma as well as other cancer types.

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Apoptosis And Resistance To Anti-Microtubule Agents

Microscopy and Microanalysis ◽

10.1017/s1431927600025307 ◽

1998 ◽

Vol 4 (S2) ◽

pp. 1036-1037

Author(s):

M. C. Willingham

Keyword(s):

Cell Death ◽

Tumor Cells ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Mitotic Spindles ◽

Trade Name ◽

Anti Cancer ◽

M Phase ◽

Target Treatment ◽

Microtubule Networks

Several clinically important anti-cancer agents exert their effects on tumor cells through interference with the function of microtubules. In addition to the Vinca alkaloids, such as vinblastine and vincristine, the taxanes, such as paclitaxel (Trade Name: Taxol), kill tumor cells through a microtubular target. Treatment with taxol leads to the inability of microtubules to depolymerize, leading to the formation of large intracellular microtubular bundles. In tumor cells that progress through the cell cycle, this leads to the inability of these cells to disassembly interphase microtubule networks and a failure to form functional mitotic spindles. These cells arrest in M phase, from which they eventually progress, either by the induction of apoptotic cell death, or by micronucleation and the formation of tetraploid cells. There is also the possibility that taxol has other effects on the regulation of genes or other systems to enhance cell killing, perhaps through lowering the threshold of cells to the induction of apoptotic cell death.

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