scholarly journals Antiproliferative and Apoptosis-Inducing Activities of Benchalokawichian Remedy Against Doxorubicin-Sensitive and -Resistant Erythromyelogenous Leukemic Cells

2021 ◽  
Vol 20 (3) ◽  
Author(s):  
Wipob Suttana ◽  
Chatubhong Singharachai ◽  
Rawiwan Charoensup ◽  
Narawadee Rujanapun ◽  
Chutima Suya
Keyword(s):  
Cell Cycle ◽  
Multidrug Resistance ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Drug Resistant ◽  
Normal Cells ◽  
Root Extracts ◽  
Cycle Arrest

Chemotherapy can cause multidrug resistance in cancer cells and is cytotoxic to normal cells. Discovering natural bioactive compounds that are not cytotoxic to normal cells but inhibit proliferation and induce apoptosis in drug- sensitive and drug-resistant cancer cells could overcome these drawbacks of chemotherapy. This study investigated the antiproliferative effects of crude extracts of Benchalokawichian (BLW) remedy and its herbal components against drug-sensitive and drug-resistant cancer cells, cytotoxicity of the extracts toward normal cells, and their ability to induce apoptosis and cell cycle arrest in drug-sensitive and drug-resistant cancer cells. The extracts exhibited antiproliferative activity against doxorubicin-sensitive and doxorubicin-resistant erythromyelogenous leukemic cells (K562 and K562/adr). Tiliacora triandra root, BLW, and Harrisonia perforata root extracts displayed an IC50 of 77.00 ± 1.30, 79.33 ± 1.33, and 87.67 ± 0.67 µg/mL, respectively, against K562 cells. In contrast, Clerodendrum petasites, T. triandra, and H. perforata root extracts displayed the lowest IC50 against K562/adr cells (68.89 ± 0.75, 78.33 ± 0.69, and 86.78 ± 1.92 µg/mL, respectively). The resistance factor of the extracts was lower than that of doxorubicin, indicating that the extracts could overcome the multidrug resistance of cancer cells. Importantly, the extracts were negligibly cytotoxic to peripheral mononuclear cells, indicating minimal adverse effects in normal cells. In addition, these extracts induced apoptosis of K562 and K562/adr cells and caused cell cycle arrest at the G0/G1 phase in K562 cells. Keywords: Antiproliferative, Apoptosis, Benchalokawichian, Cell cycle, Multidrug resistance

scholarly journals Prooxidative Activity of Celastrol Induces Apoptosis, DNA Damage, and Cell Cycle Arrest in Drug-Resistant Human Colon Cancer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Helena Moreira ◽  
Anna Szyjka ◽  
Kamila Paliszkiewicz ◽  
Ewa Barg
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Phase Cell ◽  
Drug Resistant ◽  
Cancer Resistance ◽  
Colon Cancer Cells ◽  
Cycle Arrest

Cancer resistance to chemotherapy is closely related to tumor heterogeneity, i.e., the existence of distinct subpopulations of cancer cells in a tumor mass. An important role is assigned to cancer stem cells (CSCs), a small subset of cancer cells with high tumorigenic potential and capacity of self-renewal and differentiation. These properties of CSCs are sustained by the ability of those cells to maintain a low intracellular reactive oxygen species (ROS) levels, via upregulation of ROS scavenging systems. However, the accumulation of ROS over a critical threshold disturbs CSCs—redox homeostasis causing severe cytotoxic consequences. In the present study, we investigated the capacity of celastrol, a natural pentacyclic triterpenoid, to induce the formation of ROS and, consequently, cell death of the colon cancer cells with acquired resistant to cytotoxic drugs (LOVO/DX cell line). LOVO/DX cells express several important stem-like cell features, including a higher frequency of side population (SP) cells, higher expression of multidrug resistant proteins, overexpression of CSC-specific cell surface marker (CD44), increased expression of DNA repair gene (PARP1), and low intracellular ROS level. We found that celastrol, at higher concentrations (above 1 μM), significantly increased ROS amount in LOVO/DX cells at both cytoplasmic and mitochondrial levels. This prooxidant activity was associated with the induction of DNA double-strand breaks (DSBs) and apoptotic/necrotic cell death, as well as with inhibition of cell proliferation by S phase cell cycle arrest. Coincubation with NAC, a ROS scavenger, completely reversed the above effects. In summary, our results provide evidence that celastrol exhibits effective cytotoxic effects via ROS-dependent mechanisms on drug-resistant colon cancer cells. These findings strongly suggest the potential of celastrol to effectively kill cancer stem-like cells, and thus, it is a promising agent to treat severe, resistant to conventional therapy, colon cancers.

Both G0/G1 Cell Cycle Arrest and Continuous Activation of MAPK Induce Autophagic Cell Death in bcr-abl-Positive Leukemic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4301-4301
Author(s):  
Yuko Mishima ◽  
Yasuhito Terui ◽  
Yuji Mishima ◽  
Toshihiro Takizawa ◽  
Shinya Kimura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cell Cycle Arrest ◽  
Cell Line ◽  
Immunohistochemical Analysis ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Abstract Back ground; Accumulating evidence suggests that programmed cell death is not defined as apoptosis but cells use different pathways for active self-destruction as reflected by different morphology. Autophagic cell death (APCD), which also be designated type II programmed cell death and appears to be a phylogenetically old phenomenon, is observed in physiological and disease state. Indeed, APCD is observed in several neurodegenerative diseases and cancer cells, however, the APCD in leukemic cells has not been reported yet. Here, we found APCD was occurred in bcr-abl-expressing CML cell lines. Methods; Bcr-abl-positive cell line, K562, were cultured with 2nM of TPA up to 48hours. Subsequently, we examined the morphological change by light microscopy and electronmicroscopy. To evaluate the APCD, TPA-treated K562 cells were labeled with autofluorescent agent Monodansylcadaverin(MDC), which specifically accumulates in autophagosomes and we measured accumulation of autophagosmes in cytoplasm by fluorescent microplate reader. TPA continuous activated MAPK of K562 cells and induced cell cycle arrest in G0/G1 phase. In order to elucidate the role of activation of MAPK in APCD, MAPK in K562 cells were inactivated by MAPK inhibitor, U0126 or dominant negative MAPK-transfection, and then, the cells were treated with TPA. Furthermore, to evaluate the involvement of cell cycle arrest in APCD, bcr-abl-transfected murine leukemic cell line, BAF3, was treated with cell cycle arrest inducer, mimosine. In addition, we investigated the expression of an autophagy-related molecule, Beclin 1 by immunohistochemical analysis. Result; The 48 hours’ treatment with TPA induced cell death in K562 cells, which accumulated plenty of autophagosomes in cytoplasm. MDC labeling assay revealed that accumulation of autophagosomes were increased in time- and dose-dependent manner. On the other hand, MAPK-inactivated K562 cells exhibited resistance to TPA-induced APCD. Furthermore, the bcr-abl-transfected BAF3 cells exhibited continuous activation of MAPK and underwent APCD by cell cycle arrest by mimosine. Immunohistochemical analysis revealed that Beclin 1 shuttled between nuclear and cytoplasms and co-localized with MAPK during APCD progression. Conclusion: APCD in bcr-abl-positive leukemia cells were closely involved in G0/G1 cell cycle arrest and continuous activation of MAPK. These findings are useful in developing the novel strategy to treatment of Ph1 positive leukemia via alternative pathways and another type of cell death.

scholarly journals Computational Model of G2-M DNA Damage Checkpoint Regulation in Normal and p53-null Cancer Cells

2020 ◽  
Author(s):  
Yongwoon Jung ◽  
Pavel Kraikivski
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Computational Model ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Dna Damage Checkpoint ◽  
Cycle Progression ◽  
Normal Cells ◽  
Cycle Arrest

AbstractCancer and normal cells can respond differently to the same stressful conditions. Their dynamic responses under normal and stressful conditions are governed by complex molecular regulatory networks. We developed a computational model of G2-M DNA damage checkpoint regulation to study normal and cancer cell cycle progression under normal and stressful conditions. Our model is successful in explaining cancer cell cycle arrest in conditions when some cell cycle and DNA damage checkpoint regulators are inhibited, whereas the same conditions only delay entry into mitosis in normal cells. We use the model to explain known phenotypes of gene deletion mutants and predict phenotypes of yet uncharacterized mutants in normal and cancer cells. We also use sensitive analyses to identify the ranges of model parameter values that lead to the cell cycle arrest in cancer cells. Our results can be used to predict the effect of a potential treatment on cell cycle progression of normal and cancer cells.

scholarly journals Overexpression of cyclin L2 induces apoptosis and cell-cycle arrest in human lung cancer cells

2007 ◽  
Vol 120 (10) ◽  
pp. 905-909 ◽  
Author(s):  
Hong-li LI ◽  
Tong-shan WANG ◽  
Xiao-yu LI ◽  
Nan LI ◽  
Ding-zhi HUANG ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Cycle Arrest ◽  
Human Lung Cancer Cells

scholarly journals The Antiproliferative Activity of Oxypeucedanin via Induction of G2/M Phase Cell Cycle Arrest and p53-Dependent MDM2/p21 Expression in Human Hepatoma Cells

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 501
Author(s):  
So Hyun Park ◽  
Ji-Young Hong ◽  
Hyen Joo Park ◽  
Sang Kook Lee
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Hepatoma Cells ◽  
Phase Cell ◽  
Human Hepatoma Cells ◽  
Cycle Arrest ◽  
Growth Inhibitory Activity ◽  
M Phase

Oxypeucedanin (OPD), a furocoumarin compound from Angelica dahurica (Umbelliferae), exhibits potential antiproliferative activities in human cancer cells. However, the underlying molecular mechanisms of OPD as an anticancer agent in human hepatocellular cancer cells have not been fully elucidated. Therefore, the present study investigated the antiproliferative effect of OPD in SK-Hep-1 human hepatoma cells. OPD effectively inhibited the growth of SK-Hep-1 cells. Flow cytometric analysis revealed that OPD was able to induce G2/M phase cell cycle arrest in cells. The G2/M phase cell cycle arrest by OPD was associated with the downregulation of the checkpoint proteins cyclin B1, cyclin E, cdc2, and cdc25c, and the up-regulation of p-chk1 (Ser345) expression. The growth-inhibitory activity of OPD against hepatoma cells was found to be p53-dependent. The p53-expressing cells (SK-Hep-1 and HepG2) were sensitive, but p53-null cells (Hep3B) were insensitive to the antiproliferative activity of OPD. OPD also activated the expression of p53, and thus leading to the induction of MDM2 and p21, which indicates that the antiproliferative activity of OPD is in part correlated with the modulation of p53 in cancer cells. In addition, the combination of OPD with gemcitabine showed synergistic growth-inhibitory activity in SK-Hep-1 cells. These findings suggest that the anti-proliferative activity of OPD may be highly associated with the induction of G2/M phase cell cycle arrest and upregulation of the p53/MDM2/p21 axis in SK-HEP-1 hepatoma cells.

Novel small molecule inhibitor of Kpnβ1 induces cell cycle arrest and apoptosis in cancer cells

2021 ◽  
pp. 112637
Author(s):  
Aderonke Ajayi-Smith ◽  
Pauline van der Watt ◽  
Nonkululeko Mkwanazi ◽  
Sarah Carden ◽  
John O. Trent ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Cycle Arrest ◽  
Molecule Inhibitor ◽  
Apoptosis In Cancer Cells

scholarly journals Mutant p53L194F Harboring Luminal-A Breast Cancer Cells Are Refractory to Apoptosis and Cell Cycle Arrest in Response to MortaparibPlus, a Multimodal Small Molecule Inhibitor

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3043
Author(s):  
Ahmed Elwakeel ◽  
Anissa Nofita Sari ◽  
Jaspreet Kaur Dhanjal ◽  
Hazna Noor Meidinna ◽  
Durai Sundar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Luminal A ◽  
Molecular Analyses ◽  
Cycle Arrest ◽  
Mcf 7

We previously performed a drug screening to identify a potential inhibitor of mortalin–p53 interaction. In four rounds of screenings based on the shift in mortalin immunostaining pattern from perinuclear to pan-cytoplasmic and nuclear enrichment of p53, we had identified MortaparibPlus (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) as a novel synthetic small molecule. In order to validate its activity and mechanism of action, we recruited Luminal-A breast cancer cells, MCF-7 (p53wild type) and T47D (p53L194F) and performed extensive biochemical and immunocytochemical analyses. Molecular analyses revealed that MortaparibPlus is capable of abrogating mortalin–p53 interaction in both MCF-7 and T47D cells. Intriguingly, upregulation of transcriptional activation function of p53 (as marked by upregulation of the p53 effector gene—p21WAF1—responsible for cell cycle arrest and apoptosis) was recorded only in MortaparibPlus-treated MCF-7 cells. On the other hand, MortaparibPlus-treated T47D cells exhibited hyperactivation of PARP1 (accumulation of PAR polymer and decrease in ATP levels) as a possible non-p53 tumor suppression program. However, these cells did not show full signs of either apoptosis or PAR-Thanatos. Molecular analyses attributed such a response to the inability of MortaparibPlus to disrupt the AIF–mortalin complexes; hence, AIF did not translocate to the nucleus to induce chromatinolysis and DNA degradation. These data suggested that the cancer cells possessing enriched levels of such complexes may not respond to MortaparibPlus. Taken together, we report the multimodal anticancer potential of MortaparibPlus that warrants further attention in laboratory and clinical studies.

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