Peer Review #1 of "Jellyfish extract induces apoptotic cell death through the p38 pathway and cell cycle arrest in chronic myelogenous leukemia K562 cells (v0.1)"

Chronic myeloid leukemia (CML) is a malignant tumor caused by the abnormal proliferation of hematopoietic stem cells. Among a new series of acridone derivatives previously synthesized, it was found that the methoxybenzyl 5-nitroacridone derivative 8q has nanomolar cytotoxicity in vitro against human chronic myelogenous leukemia K562 cells. In order to further explore the possible anti-leukemia mechanism of action of 8q on K562 cells, a metabolomics and molecular biology study was introduced. It was thus found that most of the metabolic pathways of the G1 phase of K562 cells were affected after 8q treatment. In addition, a concentration-dependent accumulation of cells in the G1 phase was observed by cell cycle analysis. Western blot analysis showed that 8q significantly down-regulated the phosphorylation level of retinoblastoma-associated protein (Rb) in a concentration-dependent manner, upon 48 h treatment. In addition, 8q induced K562 cells apoptosis, through both mitochondria-mediated and exogenous apoptotic pathways. Taken together, these results indicate that 8q effectively triggers G1 cell cycle arrest and induces cell apoptosis in K562 cells, by inhibiting the CDK4/6-mediated phosphorylation of Rb. Furthermore, the possible binding interactions between 8q and CDK4/6 protein were clarified by homology modeling and molecular docking. In order to verify the inhibitory activity of 8q against other chronic myeloid leukemia cells, KCL-22 cells and K562 adriamycin-resistant cells (K562/ADR) were selected for the MTT assay. It is worth noting that 8q showed significant anti-proliferative activity against these cell lines after 48 h/72 h treatment. Therefore, this study provides new mechanistic information and guidance for the development of new acridones for application in the treatment of CML.

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Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling

Oncology Letters ◽

10.3892/ol.2017.6890 ◽

2017 ◽

Cited By ~ 1

Author(s):

San-Yuan Chen ◽

Chun-Hsiang Lin ◽

Jiun-Tsai Lin ◽

Yi-Fang Cheng ◽

Han-Min Chen ◽

...

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Cell Cycle Arrest ◽

Chronic Myelogenous Leukemia ◽

K562 Cells ◽

Myelogenous Leukemia ◽

Kinase Signaling ◽

Cycle Arrest ◽

Amp Activated Protein Kinase ◽

Protein Kinase Signaling

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

PeerJ ◽

10.7717/peerj.2895 ◽

2017 ◽

Vol 5 ◽

pp. e2895 ◽

Cited By ~ 5

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.

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

Cell Death and Disease ◽

10.1038/s41419-021-04050-7 ◽

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.

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

International Journal of Genomics ◽

10.1155/2013/271347 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 22

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.

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

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504021x16130322409507 ◽

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.

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