scholarly journals Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Viktorija Juric ◽  
Lance Hudson ◽  
Joanna Fay ◽  
Cathy E. Richards ◽  
Hanne Jahns ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cortical Neurons ◽  
Apoptotic Cell ◽  
Cdk Inhibitors ◽  
Induce Cell Death ◽  
Viability Loss ◽  
Cycle Arrest ◽  
Recurrent Gbm

AbstractActivation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation or overexpression of CDKs can support tumourigenesis including glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. The incurability of GBM highlights the need to discover novel and more effective treatment options. Since CDKs 2, 7 and 9 were found to be overexpressed in GBM, we tested the therapeutic efficacy of two CDK inhibitors (CKIs) (CYC065 and THZ1) in a heterogeneous panel of GBM patient-derived cell lines (PDCLs) cultured as gliomaspheres, as preclinically relevant models. CYC065 and THZ1 treatments suppressed invasion and induced viability loss in the majority of gliomaspheres, irrespective of the mutational background of the GBM cases, but spared primary cortical neurons. Viability loss arose from G2/M cell cycle arrest following treatment and subsequent induction of apoptotic cell death. Treatment efficacies and treatment durations required to induce cell death were associated with proliferation velocities, and apoptosis induction correlated with complete abolishment of Mcl-1 expression, a cell cycle-regulated antiapoptotic Bcl-2 family member. GBM models generally appeared highly dependent on Mcl-1 expression for cell survival, as demonstrated by pharmacological Mcl-1 inhibition or depletion of Mcl-1 expression. Further analyses identified CKI-induced Mcl-1 loss as a prerequisite to establish conditions at which the BH3-only protein Bim can efficiently induce apoptosis, with cellular Bim amounts strongly correlating with treatment efficacy. CKIs reduced proliferation and promoted apoptosis also in chick embryo xenograft models of primary and recurrent GBM. Collectively, these studies highlight the potential of these novel CKIs to suppress growth and induce cell death of patient-derived GBM cultures in vitro and in vivo, warranting further clinical investigation.

scholarly journals RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Toshinori Ozaki ◽  
Akira Nakagawara ◽  
Hiroki Nagase
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Apoptotic Cell ◽  
Genetic Alterations ◽  
Apoptotic Cell Death ◽  
Cycle Arrest ◽  
Damage Response

A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such asp21WAF1,BAX, andPUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

scholarly journals Therapeutic targeting PLK1 by ON-01910.Na is effective in local treatment of retinoblastoma

2021 ◽  
Author(s):  
Huan Ma ◽  
Cong Nie ◽  
Ying Chen ◽  
Jinmiao Li ◽  
Yanjie Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Structural Integrity ◽  
Apoptotic Cell ◽  
Disease Model ◽  
Local Treatment ◽  
Three Dimensional ◽  
Cycle Arrest

Cell cycle deregulation is involved in pathogenesis of many cancers, and often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). Wehereby used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecularinhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated inboth cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor-specific and dose-dependent in retinoblastoma cells, whilst non-tumor cells wereminimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug-penetrability with multilayer cell death. Post-treatment transcriptomic findingsrevealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition, and eventually result in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantlyreduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Ourstudy is supportive that local treatment of ON-01910.Na may be a novel, effectivemodality benefiting patients with PLK1-aberrant tumors.

Propylparaben induces apoptotic cell death in human placental BeWo cells via cell cycle arrest and enhanced caspase-3 activity

2019 ◽  
Vol 16 (1) ◽  
pp. 83-92 ◽  
Author(s):  
Mi Jin Kim ◽  
Chul-Hong Kim ◽  
Mi-Jin An ◽  
Ju-Hyun Lee ◽  
Geun-Seup Shin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Bewo Cells ◽  
Cycle Arrest

Synthetic polysulfane derivatives induce cell cycle arrest and apoptotic cell death in human hematopoietic cancer cells

2014 ◽  
Vol 64 ◽  
pp. 249-257 ◽  
Author(s):  
Brigitte Czepukojc ◽  
Anne-Kathrin Baltes ◽  
Claudia Cerella ◽  
Mareike Kelkel ◽  
Uma M. Viswanathan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest ◽  
Hematopoietic Cancer

scholarly journals p53: The Attractive Tumor Suppressor in the Cancer Research Field

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Toshinori Ozaki ◽  
Akira Nakagawara
Keyword(s):  
Cell Cycle ◽  
Cancer Research ◽  
Cell Death ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Apoptotic Cell ◽  
Genetic Alterations ◽  
Research Field ◽  
Apoptotic Cell Death ◽  
Cycle Arrest

p53 is one of the most studied tumor suppressors in the cancer research field. Of note, over 50% of human tumors carry loss of function mutations, and thus p53 has been considered to be a classical Knudson-type tumor suppressor. From the functional point of view, p53 is a nuclear transcription factor to transactivate a variety of its target genes implicated in the induction of cell cycle arrest, DNA repair, and apoptotic cell death. In response to cellular stresses such as DNA damage, p53 is activated and promotes cell cycle arrest followed by the replacement of DNA lesions and/or apoptotic cell death. Therefore, p53 is able to maintain the genomic integrity to prevent the accumulation of genetic alterations, and thus stands at a crossroad between cell survival and cell death. In this paper, we describe a variety of molecular mechanisms behind the regulation of p53.

scholarly journals Nomad Jellyfish Rhopilema nomadica Venom Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Hepatocellular Carcinoma HepG2 Cells

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5185
Author(s):  
Mohamed M. Tawfik ◽  
Nourhan Eissa ◽  
Fayez Althobaiti ◽  
Eman Fayad ◽  
Ali H. Abu Almaaty
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Dna Fragmentation ◽  
Hepg2 Cells ◽  
Apoptotic Cell ◽  
Cycle Arrest ◽  
Jellyfish Venom

Jellyfish venom is a rich source of bioactive proteins and peptides with various biological activities including antioxidant, antimicrobial and antitumor effects. However, the anti-proliferative activity of the crude extract of Rhopilema nomadica jellyfish venom has not been examined yet. The present study aimed at the investigation of the in vitro effect of R. nomadica venom on liver cancer cells (HepG2), breast cancer cells (MDA-MB231), human normal fibroblast (HFB4), and human normal lung cells (WI-38) proliferation by using MTT assay. The apoptotic cell death in HepG2 cells was investigated using Annexin V-FITC/PI double staining-based flow cytometry analysis, western blot analysis, and DNA fragmentation assays. R. nomadica venom displayed significant dose-dependent cytotoxicity on HepG2 cells after 48 h of treatment with IC50 value of 50 μg/mL and higher toxicity (3:5-fold change) against MDA-MB231, HFB4, and WI-38 cells. R. nomadica venom showed a prominent increase of apoptosis as revealed by cell cycle arrest at G2/M phase, upregulation of p53, BAX, and caspase-3 proteins, and the down-regulation of anti-apoptotic Bcl-2 protein and DNA fragmentation. These findings suggest that R. nomadica venom induces apoptosis in hepatocellular carcinoma cells. To the best of the authors’ knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest of R. nomadica jellyfish venom.

The MDM2 Antagonist Nutlin-3 Is Effective to Aggressive NK-Cell Neoplasms with Wild Type p53 in Hypoxia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4999-4999
Author(s):  
Yoko Tabe ◽  
Yasushi Isobe ◽  
Koichi Sugimoto ◽  
Linhua Jin ◽  
Kazuo Oshimi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Nk Cell ◽  
Apoptotic Cell ◽  
Annexin V ◽  
Wild Type ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Abstract Abstract 4999 Natural killer (NK) cell neoplasms, including extranodal NK/T-cell lymphoma, nasal type (ENKL) and aggressive NK cell leukemia (ANKL), show a highly aggressive clinical course with poor response to chemotherapy, and new treatment approaches are urgently needed to improve cure rates. Patients with NK cell neoplasms cluster in Asia and Latin American countries, and the frequency of p53 mutations has been reported to be various by district. We have demonstrated that MDM2 protein was overexpressed in aggressive subclasses of NK cell neoplasms (Sugimoto et al. Jap J Cancer Res. 2002), which suggests that wild-type p53 expressing malignant NK cells may be a good candidate for biologic therapies that abrogate MDM2-p53 interactions and lead to cell death. Nutlin-3 is a small-molecule antagonist of MDM2 that efficiently blocks the MDM2-p53 interaction. In this study, we investigated the effects of nutlin-3 in 3 cell lines of ENKL and ANKL with known p53 mutation status (wt-p53: NK-YS, HANK-1; mt-p53: KHYG-1). Since aggressive NK-cell neoplasms arise in hypoxic environments and usually show an angiodestructive-infiltration pattern resulting in the tissue necrosis, we tried to assess the anti-proliferative effects and molecular mechanisms of nutlin-3 in the hypoxic condition. For hypoxia experiments, cells were cultured under 1.0% O2 for at least 14 days to assure their continuous proliferation and survival. Under hypoxia, more cells were positive to Annexin V than in normoxia, indicating that hypoxic conditions promote apoptosis in NK cell neoplasms. Nutlin-3 treatment in normoxia resulted in a reduction of cell proliferation with G0/G1 cell cycle arrest in a time and concentration-dependent manner in wt-p53 cells (IC50 at 48 hrs; 3.2 μM for NK-YS and 5.0 μM for HANK-1, MTT test). In hypoxia, nutlin-3 further enhanced cell growth inhibition and G0/G1 cell cycle arrest. An increase in the specific apoptosis (sub G1 and annexin V positivity) by nutlin-3 was observed with similar level between normoxia and hypoxia. The mt-p53 KHYG-1 cells demonstrated neither cell cycle arrest nor increase in the apoptotic cell fraction after nutlin-3 treatment. In the wt-p53 NK-YS and HANK-1 cells, nutlin-3 treatment increased the cellular levels of p53, and p53 dependent proteins including p21, MDM2 itself and the proapoptotic BH3-only proteins Noxa and Puma followed by the activation of caspase-9 and caspase-3 regardless of foxygen level. We observed no significant increase in the p53 targets in the mt-p53 overexpressing KHYG-1 cells. L-asparaginase has been demonstrated to induce apoptosis in aggressive NK cell neopplasms. To determine if inhibition of the TP53-MDM2 interaction by nutlin-3 in NK cell neoplasms might potentiate the effects of L-asparaginase, we assessed the effect of combining the two drugs. However, L-asparaginase induced apoptosis only in NK-YS cells, and no synergistic anti-proliferative effect was observed in any of the cell lines analyzed. These findings demonstrate that nutlin-3 successfully activates wt-p53 in NK cell neoplasms leading to the upregulation of traditional targets such as p21 and proapoptotic proteins including Noxa and Puma, and result in apoptotic cell death regardless of oxygen concentration. The data suggest that p53 activators such as nutlin-3 may be considerable for selected patients with wt-p53 NK cell neoplasms. Disclosures: No relevant conflicts of interest to declare.

Taxol-Induced Apoptosis May Occur Via a Signaling Pathway Independent of Microtubule Bundling and Cell Cycle Arrest

1998 ◽  
Vol 4 (S2) ◽  
pp. 1042-1043
Author(s):  
Weimin Fan ◽  
Merrill C. Miller III ◽  
Lirong Cheng ◽  
Mark C. Willingham
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Tumor Cells ◽  
Apoptotic Cell ◽  
Metastatic Breast ◽  
Mitotic Arrest ◽  
Cycle Arrest ◽  
Human Solid Tumors ◽  
Induced Apoptosis

Taxol, a plant-derived antimicrotubule agent, was originally isolated from the bark of the Pacific yew, Taxus brevifolia. This naturally occurring antineoplastic drug has been demonstrated to possess broad activity against a variety of human solid tumors, particularly in drug-refractory ovarian cancer and metastatic breast cancer (1). However, the exact mechanism of taxol's cytotoxicity against tumor cells is not entirely clear. Recent studies have demonstrated that taxol, besides causing microtubule bundling and mitotic arrest, is able to induce internucleosomal DNA fragmentation and typical morphological features of apoptosis in a number of solid tumor cells. These results clearly indicate that taxol, in addition to its classical activity against microtubules and cell cycle arrest, also possesses significant cell-killing activity by induction of apoptosis.Although it is well recognized that taxol can cause both mitotic arrest and apoptotic cell death, it remains unclear whether taxol-induced cell death is a secondary event resulting from mitotic arrest or represents a novel mechanism of taxol against tumor cells.

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