scholarly journals Effects of annexin A1 on apoptosis and cell cycle arrest in human leukemic cell lines

2019 ◽  
Vol 69 (1) ◽  
pp. 75-86 ◽  
Author(s):  
Affidah Sabran ◽  
Endang Kumolosasi ◽  
Ibrahim Jantan
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Leukemic Cell ◽  
Jurkat Cells ◽  
G1 Phase ◽  
U937 Cells ◽  
Annexin A1 ◽  
Leukemic Cell Lines ◽  
Cycle Arrest ◽  
Induced Apoptosis

Abstract Recent studies suggest that annexin A1 (ANXA1) promotes apoptosis in cancerous cells. This study aims to investigate the effects of ANXA1 on apoptosis and cell cycle arrest in K562, Jurkat and U937 cells and peripheral blood mononu-clear cells (PBMC). Cells were treated with ANXA1 and cyclophosphamide prior to flow cytometry analysis for apoptosis and cell cycle arrest induction. At 2.5µM, ANXA1 induced significant apoptosis in K562 (p ≤ 0.001) and U937 (p ≤ 0.05) cells, with EC50 values of 3.6 and 3.8 µM, respectively. In Jurkat cells, induction was not significant (EC50, 17.0 µM). No significant apoptosis induction was observed in PBMC. ANXA1 caused cycle arrest in the G0/G1 phase in K562 and U937 cells with p ≤ 0.001 for both, and (p ≤ 0.01) for Jurkat cells. ANXA1 induced apoptosis and cycle arrest in the G0/G1 phase in K562 and U937 cells, causing only cell cycle arrest in Jurkat cells.

JNK/c-Jun Is Required for HMC-1 Cell Proliferation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4439-4439
Author(s):  
Bin Wang ◽  
Junichi Tsukada ◽  
Takehiro Higashi ◽  
Takamitsu Mizobe ◽  
Ai Matsuura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Mast Cells ◽  
Cell Cycle Arrest ◽  
Caspase 3 ◽  
Cyclin D3 ◽  
G1 Phase ◽  
Caspase 9 ◽  
Cycle Arrest ◽  
Induced Apoptosis

Abstract Activation of c-jun N-terminal kinase (JNK) through c-kit-mediated phosphatidylinositol 3 (PI3) and Src kinase pathways plays an important role in cell proliferation and survival in mast cells. Gain-of-function mutations in c-kit are found in several human neoplasms. Constitutive activation of c-kit has been observed in human mastocytosis, acute myeloid leukemia, lymphoma, germ tumor and gastrointestinal stromal tumor. In the present study, we demonstrate that an anthrapyrazole SP600125, a reversible ATP-competitive inhibitor of JNK inhibits proliferation of human HMC-1 mast cells expressing constitutively activated c-kit mutant. We found that JNK/c-Jun was constitutively activated in HMC-1 cells without stimulation. When spontaneous activation of JNK/c-Jun was inhibited by treatment with SP600125, cell proliferation was suppressed. The concentration which effectively inhibited JNK/c-Jun activity in our experiment had no effect on SCF-induced phosphorylation of Akt or Erk, suggesting that SP600125 specifically inhibited JNK/c-Jun activity in HMC-1 cells. Moreover, we demonstrated that SP600125 induced HMC-1 cell apoptosis in dose- and time-dependent manner. Caspase-3 and PARP were cleaved as early as 12 h after treatment with SP600125, but caspase-9 was not. Also, cell cycle arrest in G1 phase was observed in SP600125 treated cells. Thus, the inhibitory effect of SP600125 on cell proliferation was associated with cell cycle arrest at the G1 phase and apoptosis accompanied by cleavage of caspase-3 and PARP. Caspase-3 inhibitor Z-DEVD-FMK almost completely inhibited SP600125-induced apoptosis of HMC-1 cells. In contrast, caspase-9 inhibitor Z-LEHD-FMK failed to block SP600125-induced apoptosis, suggesting that apoptosis induced by SP600125 was caspase-3 dependent. Following SP600125 treatment, down-regulation of cyclin D3 protein expression, but not p53 was also observed. Take together, JNK/c-Jun is essential for proliferation and survival of HMC-1 cells. The results obtained from the present study suggest the possibility that JNK/c-Jun may be a therapeutic target in diseases associated with c-kit mutant.

Polycystin-1 induced apoptosis and cell cycle arrest in G0/G1 phase in cancer cells

2008 ◽  
Vol 32 (4) ◽  
pp. 427-435 ◽  
Author(s):  
Rong Zheng ◽  
Zheng Zhang ◽  
Xiaoyan Lv ◽  
JunMing Fan ◽  
Ye Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
G1 Phase ◽  
Cycle Arrest ◽  
Induced Apoptosis

scholarly journals Selective Targeting of Class1 Histone Deacetylase (HDAC) Isoforms by a Novel Inhibitor SBAK-GHA Potently Resist Leukemogenesis

2020 ◽  
Author(s):  
Javeed Ahmad Bhat ◽  
Nawab John Dar ◽  
Mudassier Ahmad ◽  
Mubashir Javed Mintoo ◽  
Rauf Ahmad Najar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Histone Acetylation ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Hdac Inhibitor ◽  
Leukemic Cell ◽  
Class I ◽  
Leukemic Cell Lines ◽  
Cycle Arrest

Abstract Background: Acute promyelocytic leukemia (APL) and acute lymphoblastic leukaemia (ALL) are often presented with loss of H4K16 monoacetylation (ac) and H4K20 trimethylation (3Me) due to increased activity of Class I HDAC’s. In the current study we explored the efficacy and mechanistic basis of a novel Class I HDAC inhibitor SBAK-GHA across different leukemic cell lines and characterised the distinct acetylation pattern on histone H3 and H4.Methods: We initially performed general and class specific HDAC enzyme activity assays to establish the effect of our lead molecule SBAK-GHA. Following, we have probed various acetylation sites to understand a thorough acetylation profile of various leukemic cell lines by immunoblotting. Next, to understand the effect of various Class 1 HDAC isoforms on acetylation levels of hallmark proteins in leukaemia; lentiviral knockdown approach was carried out. In addition, cell cycle analysis was also done to distinguish the pattern of cell cycle phase arrest, followed by Chip-qPCR studies of various cyclins and their relationship with cell cycle arrest. Finally, an in vivo study was performed to confirm the anti-leukemic activity of SBAK-GHA by using specific leukaemia models.Results: SBAK-GHA showed class I HDAC inhibitor activity specifically targeting HDAC 2. SBAK-GHA treatment upregulates H4K16 ac and H4K20 me3 in variety of leukemic cell lines. Similar results were found during knock down of HDAC2 in leukemic cell lines. Moreover, we also observed a coherence of events like cell cycle arrest across different cell types of leukemias and modulation in the levels of acetylation across different cyclin promoters. Further on, studies in various in vivo cancer models demonstrated SBAK-GHA to be highly selective towards lymphocytic leukaemia.Conclusion: Our data provided a basic overview of relationship between different class I HDAC isoforms and their possible roles in regulation of histone acetylation in pathogenesis of leukaemia. Our study here presented multiple evidences regarding SBAK-GHA as a novel HDAC2 inhibitor. SBAK-GHA resist leukemogenesis mainly by inducing the repressed H4K16 ac and H4K20 me3. Further, the results in present study had established a relationship between class I HDAC isoforms and their possible roles in regulation of histone acetylation in pathogenesis of leukaemia.

scholarly journals G1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3845
Author(s):  
Shin Young Park ◽  
Ki Yun Kim ◽  
Do Youn Jun ◽  
Su-Kyeong Hwang ◽  
Young Ho Kim
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Jurkat Cells ◽  
Parp Cleavage ◽  
Caspase 8 ◽  
Down Regulation ◽  
Blocking Antibody ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Induced Apoptosis

In vitro antitumor activity of the CDK7 inhibitor BS-181 against human T-ALL Jurkat cells was determined. Treatment of Jurkat clones (JT/Neo) with BS-181 caused cytotoxicity and several apoptotic events, including TRAIL/DR4/DR5 upregulation, c-FLIP down-regulation, BID cleavage, BAK activation, ΔΨm loss, caspase-8/9/3 activation, and PARP cleavage. However, the BCL-2-overexpressing Jurkat clone (JT/BCL-2) abrogated these apoptotic responses. CDK7 catalyzed the activating phosphorylation of CDK1 (Thr161) and CDK2 (Thr160), and CDK-directed retinoblastoma phosphorylation was attenuated in both BS-181-treated Jurkat clones, whereas only JT/BCL-2 cells exhibited G1 cell cycle arrest. The G1-blocker hydroxyurea augmented BS-181-induced apoptosis by enhancing TRAIL/DR4/DR5 upregulation and c-FLIP down-regulation. BS-181-induced FITC–annexin V-positive apoptotic cells were mostly in the sub-G1 and G1 phases. BS-181-induced cytotoxicity and mitochondrial apoptotic events (BAK activation/ΔΨm loss/caspase-9 activation) in Jurkat clones I2.1 (FADD-deficient) and I9.2 (caspase-8-deficient) were significantly lower than in A3 (wild-type). Exogenously added recombinant TRAIL (rTRAIL) markedly synergized BS-181-induced apoptosis in A3 cells but not in normal peripheral T cells. The cotreatment cytotoxicity was significantly reduced by the DR5-blocking antibody but not by the DR4-blocking antibody. These results demonstrated that the BS-181 anti-leukemic activity is attributed to extrinsic TRAIL/DR5-dependent apoptosis preferentially induced in G1-arrested cells, and that BS-181 and rTRAIL in combination may hold promise for T-ALL treatment.

Ligand Activation of FLT3 Induces Cell Cycle Arrest in Acute Lymphoblastic Leukemia with 11q23 Translocation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1888-1888
Author(s):  
Yoshiyuki Furuichi ◽  
Kanji Sugita ◽  
Takeshi Inukai ◽  
Kumiko Goi ◽  
Kazuya Takahashi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Hematopoietic Stem ◽  
Leukemic Cell Lines ◽  
Cycle Arrest

Abstract A fms-like kinase (FLT3) is widely known to be involved in proliferation of normal hematopoietic stem cells and precursors. Acute lymphoblastic leukemia (ALL) with 11q23 translocation, often found in infantile leukemia with very poor prognosis, is thought to be derived from a population of cells at the developmental stage very close to hematopoietic stem cells, and was recently shown that they express FLT3 at high levels compared with other types of leukemia. In the present study, we examined the effects of FLT3 ligand (FL) on leukemia cells with or without 11q23 translocation to evaluate a biological implication of the FLT3/FL interaction in ALL. Three of 8 leukemic cell lines without 11q23 translocation showed a proliferative response to FL in the 3H-thymidine uptake assays. However, five of 7 B-precursor leukemic cell lines with 11q23 translocation, unexpectedly, showed an inhibitory response (23-69% inhibition) to FL in a dose-dependent manner (1–20ng/ml), although the special cell line with D835 mutation in FLT3 (KOCL-33) was not affected by the addition of FL. This inhibitory effect was almost abrogated in the presence of a FLT-3 kinase inhibitor PKC412. Inhibition of 3H-thymidine uptakes were not due to induction of apoptosis but due to induction of the Go/G1 arrest. This cell cycle arrest was mediated, at least in part, by a marked up-regulation of p27 due to suppression of its degradation, and promoted resistance of cell lines to radiation-induced apoptosis. Of interest, the addition of FL induced a complete disappearance of constitutive phosphorylation of STAT5 but upregulated phosphorylation of MAPK and Akt. These results suggest that the FLT3/FL interaction in ALL with 11q23 translocation transmits the inhibitory signal specifically to the JAK/STAT pathway via the kinase activity of FLT3, in the process of which the JAK/STAT-specific inhibitory molecules such as SOCS-2 and CIS-1 may be implicated.

scholarly journals Jellyfish extract induces apoptotic cell death through the p38 pathway and cell cycle arrest in chronic myelogenous leukemia K562 cells

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e2895 ◽  
Author(s):  
Sun-Hyung Ha ◽  
Fansi Jin ◽  
Choong-Hwan Kwak ◽  
Fukushi Abekura ◽  
Jun-Young Park ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Chronic Myelogenous Leukemia ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
G1 Phase ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Induced Apoptosis ◽  
Cancer Activity

Jellyfish species are widely distributed in the world’s oceans, and their population is rapidly increasing. Jellyfish extracts have several biological functions, such as cytotoxic, anti-microbial, and antioxidant activities in cells and organisms. However, the anti-cancer effect of Jellyfish extract has not yet been examined. We used chronic myelogenous leukemia K562 cells to evaluate the mechanisms of anti-cancer activity of hexane extracts from Nomura’s jellyfish in vitro. In this study, jellyfish are subjected to hexane extraction, and the extract is shown to have an anticancer effect on chronic myelogenous leukemia K562 cells. Interestingly, the present results show that jellyfish hexane extract (Jellyfish-HE) induces apoptosis in a dose- and time-dependent manner. To identify the mechanism(s) underlying Jellyfish-HE-induced apoptosis in K562 cells, we examined the effects of Jellyfish-HE on activation of caspase and mitogen-activated protein kinases (MAPKs), which are responsible for cell cycle progression. Induction of apoptosis by Jellyfish-HE occurred through the activation of caspases-3,-8 and -9 and phosphorylation of p38. Jellyfish-HE-induced apoptosis was blocked by a caspase inhibitor, Z-VAD. Moreover, during apoptosis in K562 cells, p38 MAPK was inhibited by pretreatment with SB203580, an inhibitor of p38. SB203580 blocked jellyfish-HE-induced apoptosis. Additionally, Jellyfish-HE markedly arrests the cell cycle in the G0/G1 phase. Therefore, taken together, the results imply that the anti-cancer activity of Jellyfish-HE may be mediated apoptosis by induction of caspases and activation of MAPK, especially phosphorylation of p38, and cell cycle arrest at the Go/G1 phase in K562 cells.

scholarly journals Ropivacaine induces cell cycle arrest in the G0/G1 phase and apoptosis of PC12 cells via inhibiting mitochondrial STAT3 translocation

2021 ◽  
Author(s):  
Lian Zeng ◽  
Zhen Zhang ◽  
Fuyu Zhang ◽  
Huaxian Chen ◽  
Ying Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Spinal Cord ◽  
Cell Cycle Arrest ◽  
Pc12 Cells ◽  
Neuroprotective Effect ◽  
G1 Phase ◽  
Upstream Gene ◽  
Mitochondrial Translocation ◽  
Cycle Arrest ◽  
Induced Apoptosis

Abstract STAT3 has neuroprotective effect via non-canonical activation and mitochondrial translocation, but its effects on ropivacaine-induced neurotoxicity remain unclear. Our previous study revealed that apoptosis was an important mechanism of ropivacaine-induced neurotoxicity, this study is to illustrate the relationship between STAT3 with ropivacaine-induced apoptosis. Those results showed that ropivacaine treatment decreased cell viability, induced cell cycle arrest in the G0/G1 phase, apoptosis, oxidative stress, and mitochondrial dysfunction in PC12 cells. Besides, ropivacaine decreased the phosphorylated levels of STAT3 at Ser727 and downregulated the expression of STAT3 upstream gene IL-6. The mitochondrial translocation of STAT3 was also hindered by ropivacaine. To further illustrate the connection of STAT3 protein structure with ropivacaine, the autodock-vina was used to examine the interaction between STAT3 and ropivacaine, and the results showed that ropivacaine could bind to STAT3’s proline site and other sites. In addition, the activator and inhibitor of mitoSTAT3 translocation were used to demonstrate it was involved in ropivacaine-induced apoptosis, the results showed that enhancing the mitochondrial STAT3 translocation could prevent ropivacaine-induced apoptosis. Finally, the expression of p-STAT3 and the levels of apoptosis in the spinal cord were also detected, the results were consistent with the cell experiment, ropivacaine decreased the expression of p-STAT3 protein and increased the levels of apoptosis in the spinal cord. We demonstrated that ropivacaine induced apoptosis by inhibiting the phosphorylation of STAT3 at Ser727 and the mitochondrial STAT3 translocation. This effect was reversed by the activation of the mitochondrial STAT3 translocation.

Synergistic Effect of α-Solanine and Cisplatin Induces Apoptosis and Enhances Cell Cycle Arrest in Human Hepatocellular Carcinoma Cells

2020 ◽  
Vol 19 (18) ◽  
pp. 2197-2210 ◽  
Author(s):  
Sherien M. El-Daly ◽  
Shaimaa A. Gouhar ◽  
Amira M. Gamal-Eldeen ◽  
Fatma F. Abdel Hamid ◽  
Magdi N. Ashour ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Synergistic Effect ◽  
Cell Cycle Arrest ◽  
Combination Treatment ◽  
Carcinoma Cells ◽  
Cell Growth Inhibition ◽  
Cycle Arrest ◽  
Induced Apoptosis ◽  
Human Hepatocellular Carcinoma Cells

Aim: The clinical application of cisplatin is limited by severe side effects associated with high applied doses. The synergistic effect of a combination treatment of a low dose of cisplatin with the natural alkaloid α-solanine on human hepatocellular carcinoma cells was evaluated. Methods: HepG2 cells were exposed to low doses of α-solanine and cisplatin, either independently or in combination. The efficiency of this treatment modality was evaluated by investigating cell growth inhibition, cell cycle arrest, and apoptosis enhancement. Results: α-solanine synergistically potentiated the effect of cisplatin on cell growth inhibition and significantly induced apoptosis. This synergistic effect was mediated by inducing cell cycle arrest at the G2/M phase, enhancing DNA fragmentation and increasing apoptosis through the activation of caspase 3/7 and/or elevating the expression of the death receptors DR4 and DR5. The induced apoptosis from this combination treatment was also mediated by reducing the expression of the anti-apoptotic mediators Bcl-2 and survivin, as well as by modulating the miR-21 expression. Conclusion: Our study provides strong evidence that a combination treatment of low doses of α-solanine and cisplatin exerts a synergistic anticancer effect and provides an effective treatment strategy against hepatocellular carcinoma.

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