scholarly journals Antiproliferative Effect of Dihydroxyacetone on Trypanosoma brucei Bloodstream Forms: Cell Cycle Progression, Subcellular Alterations, and Cell Death

2007 ◽  
Vol 51 (11) ◽  
pp. 3960-3968 ◽  
Author(s):  
Néstor L. Uzcátegui ◽  
Didac Carmona-Gutiérrez ◽  
Viola Denninger ◽  
Caroline Schoenfeld ◽  
Florian Lang ◽  
...  
Keyword(s):  
Energy Source ◽  
Cell Cycle ◽  
Trypanosoma Brucei ◽  
Rational Design ◽  
Cell Cycle Progression ◽  
Cell Types ◽  
Cycle Arrest ◽  
Starting Point ◽  
M Phase ◽  
Different Cell Types

ABSTRACT We evaluated the effects of dihydroxyacetone (DHA) on Trypanosoma brucei bloodstream forms. DHA is considered an energy source for many different cell types. T. brucei takes up DHA readily due to the presence of aquaglyceroporins. However, the parasite is unable to use it as a carbon source because of the absence of DHA kinase (DHAK). We could not find a homolog of the relevant gene in the genomic database of T. brucei and have been unable to detect DHAK activity in cell lysates of the parasite, and the parasite died quickly if DHA was the sole energy source in the medium. In addition, during trypanosome cultivation, DHA induced growth inhibition with a 50% inhibitory concentration of about 1 mM, a concentration that is completely innocuous to mammals. DHA caused cell cycle arrest in the G2/M phase of up to 70% at a concentration of 2 mM. Also, DHA-treated parasites showed profound ultrastructural alterations, including an increase of vesicular structures within the cytosol and the presence of multivesicular bodies, myelin-like structures, and autophagy-like vacuoles, as well as a marked disorder of the characteristic mitochondrion structure. Based on the toxicity of DHA for trypanosomes compared with mammals, we consider DHA a starting point for a rational design of new trypanocidal drugs.

scholarly journals Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis

2018 ◽  
Vol 315 (2) ◽  
pp. L162-L172 ◽  
Author(s):  
David W. Waters ◽  
Kaj E. C. Blokland ◽  
Prabuddha S. Pathinayake ◽  
Janette K. Burgess ◽  
Steven E. Mutsaers ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Wound Repair ◽  
Cell Cycle Progression ◽  
Early Stage ◽  
Critical Role ◽  
Cell Types ◽  
Normal Fibroblast ◽  
Cycle Arrest

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause with a median survival of only three years. Little is known about the mechanisms that precede the excessive collagen deposition seen in IPF, but cellular senescence has been strongly implicated in disease pathology. Senescence is a state of irreversible cell-cycle arrest accompanied by an abnormal secretory profile and is thought to play a critical role in both development and wound repair. Normally, once a senescent cell has contributed to wound repair, it is promptly removed from the environment via infiltrating immune cells. However, if immune clearance fails, the persistence of senescent cells is thought to drive disease pathology through their altered secretory profile. One of the major cell types involved in wound healing is fibroblasts, and senescent fibroblasts have been identified in the lungs of patients with IPF and in fibroblast cultures from IPF lungs. The question of what is driving abnormally high numbers of fibroblasts into senescence remains unanswered. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a role in a myriad of processes, including cell-cycle progression, gene transcription, as well as mitochondrial respiration, all of which are dysregulated during senescence. Activation of STAT3 has previously been shown to correlate with IPF progression and therefore is a potential molecular target to modify early-stage senescence and restore normal fibroblast function. This review summarizes what is presently known about fibroblast senescence in IPF and how STAT3 may contribute to this phenotype.

scholarly journals Ddb1 Is Essential for the Expansion of CD4+ Helper T Cells by Regulating Cell Cycle Progression and Cell Death

2021 ◽  
Vol 12 ◽  
Author(s):  
Lingtao Yang ◽  
Wei Chen ◽  
Li Li ◽  
Yueyue Xiao ◽  
Shilin Fan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cell Death ◽  
Cell Cycle Progression ◽  
Helper T Cells ◽  
Genome Maintenance ◽  
Cycle Arrest ◽  
Follicular Helper ◽  
Acute Viral Infection ◽  
M Phase

Follicular helper T (TFH) cells are specialized CD4+ helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of TFH cells is incompletely understood. Here, we reported that Damage-specific DNA binding protein 1 (Ddb1) was required for expansion of CD4+ helper T cells including TFH and Th1 cells, germinal center response, and antibody response to acute viral infection. Ddb1 deficiency in activated CD4+ T cells resulted in cell cycle arrest at G2-M phase and increased cell death, due to accumulation of DNA damage and hyperactivation of ATM/ATR-Chk1 signaling. Moreover, mice with deletion of both Cul4a and Cul4b in activated CD4+ T cells phenocopied Ddb1-deficient mice, suggesting that E3 ligase-dependent function of Ddb1 was crucial for genome maintenance and helper T-cell generation. Therefore, our results indicate that Ddb1 is an essential positive regulator in the expansion of CD4+ helper T cells.

scholarly journals Early Induction of Apoptosis in Hematopoietic Cell Lines After Exposure to Flavopiridol

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 458-465 ◽  
Author(s):  
Bernard W. Parker ◽  
Gurmeet Kaur ◽  
Wilberto Nieves-Neira ◽  
Mohammed Taimi ◽  
Glenda Kohlhagen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Prostate Carcinoma ◽  
Cell Types ◽  
Carcinoma Cells ◽  
Cycle Arrest ◽  
Induced Apoptosis ◽  
Different Cell Types ◽  
Hematopoietic Cell Lines

Abstract Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4:120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (IC50). Flavopiridol did not induce topoisomerase I or II cleavable complex activity. A relation of p53, bcl2, or bax protein levels to apoptosis in SUDHL4 was not appreciated. While flavopiridol caused cell cycle arrest with decline in CDK1 activity in PC3 cells, apoptosis of SUDHL4 cells occurred without evidence of cell cycle arrest. These results suggest that antiproliferative activity of flavopiridol (manifest by cell cycle arrest) may be separated in different cell types from a capacity to induce apoptosis. Cells from hematopoietic neoplasms appear in this limited sample to be very susceptible to flavopiridol-induced apoptosis and therefore clinical trials in hematopoietic neoplasms should be of high priority.

scholarly journals Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1996 ◽  
Author(s):  
Bartolomeo Bosco ◽  
Andrea Defant ◽  
Andrea Messina ◽  
Tania Incitti ◽  
Denise Sighel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Density Functional ◽  
Cell Cycle Progression ◽  
Cycle Arrest ◽  
M Phase

Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1–3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1–3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.

scholarly journals Selenium supplementation protects against oxidative stress-induced cardiomyocyte cell cycle arrest through activation of PI3K/AKT

Metallomics ◽  
2020 ◽  
Author(s):  
Wenjuan Sun ◽  
Jiawei Zhu ◽  
Shuang Li ◽  
Chaohua Tang ◽  
Qingyu Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Inhibitory System ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
System P ◽  
M Phase ◽  
Promote Cell Cycle Progression

Selenium alleviates oxidative stress-induced cell cycle arrest in cardiomyocytes mediated by antioxidant capacity of selenoproteins, thus activating PI3K/AKT pathways, which promote cell cycle progression by targeting the G2/M phase inhibitory system.

scholarly journals Early Induction of Apoptosis in Hematopoietic Cell Lines After Exposure to Flavopiridol

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 458-465 ◽  
Author(s):  
Bernard W. Parker ◽  
Gurmeet Kaur ◽  
Wilberto Nieves-Neira ◽  
Mohammed Taimi ◽  
Glenda Kohlhagen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Prostate Carcinoma ◽  
Cell Types ◽  
Carcinoma Cells ◽  
Cycle Arrest ◽  
Induced Apoptosis ◽  
Different Cell Types ◽  
Hematopoietic Cell Lines

Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4:120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (IC50). Flavopiridol did not induce topoisomerase I or II cleavable complex activity. A relation of p53, bcl2, or bax protein levels to apoptosis in SUDHL4 was not appreciated. While flavopiridol caused cell cycle arrest with decline in CDK1 activity in PC3 cells, apoptosis of SUDHL4 cells occurred without evidence of cell cycle arrest. These results suggest that antiproliferative activity of flavopiridol (manifest by cell cycle arrest) may be separated in different cell types from a capacity to induce apoptosis. Cells from hematopoietic neoplasms appear in this limited sample to be very susceptible to flavopiridol-induced apoptosis and therefore clinical trials in hematopoietic neoplasms should be of high priority.

Cyclization of flavokawain B reduces its activity against human colon cancer cells

2019 ◽  
Vol 39 (3) ◽  
pp. 262-275 ◽  
Author(s):  
A Palko-Łabuz ◽  
E Kostrzewa-Susłow ◽  
T Janeczko ◽  
K Środa-Pomianek ◽  
A Poła ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Structural Parameters ◽  
Human Colon ◽  
Human Colon Cancer ◽  
Cycle Arrest ◽  
Biological Studies ◽  
M Phase ◽  
Induced Apoptosis

Chalcones are naturally occurring compounds exhibiting biological activity through multiple mechanisms. Flavokawain B is one of chalcones found in kava plant. In our studies, we focused on the anticancer activity of flavokawain B in colorectal cancer cells LoVo and its resistant to doxorubicin subline—LoVo/Dx. Strong cytotoxic activity of flavokawain B and its ability to inhibit the proliferation in both cell lines was detected. These effects accompanied with induction cell cycle arrest in G2/M phase and the presence of SubG1 fraction. Flavokawain B at low concentration led to increase of caspase-3 activity. The chalcone-induced apoptosis was also confirmed by DNA fragmentation. In our work, the conversion of flavokawain B to corresponding flavanone—5,7-dimetoxyflavanone—was shown to be more extensive in cancer than in non-cancer cells. We found that the cyclization of the chalcone was related to the significant decrease in the cytotoxicity. Cell proliferation and cell cycle progression were not impaired significantly in the studied cancer cells incubated with 5,7-dimethoxyflavanone. We did not observe apoptosis in the cells incubated with flavanone. The results from biological studies agreed with the theoretical activity that emerges from structural parameters.

scholarly journals BmFoxO Gene Regulation of the Cell Cycle Induced by 20-Hydroxyecdysone in BmN-SWU1 Cells

Insects ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 700
Author(s):  
Qian Zhang ◽  
Jigui Yang ◽  
Peng Chen ◽  
Taihang Liu ◽  
Qin Xiao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Nuclear Translocation ◽  
G1 Phase ◽  
Ecdysone Receptor ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Cell Accumulation ◽  
M Phase

Ecdysteroid titer determines the state of the cell cycle in silkworm (Bombyxmori) metamorphosis. However, the mechanism of this process is unclear. In this study, we demonstrated that the BmFoxO gene participates in the regulation of the cell cycle induced by 20-Hydroxyecdysone (20E) in BmN-SWU1 cells. The 20E blocks the cell cycle in the G2/M phase through the ecdysone receptor (EcR) and inhibits DNA replication. The 20E can promote BmFoxO gene expression. Immunofluorescence and Western blot results indicated that 20E can induce BmFoxO nuclear translocation in BmN-SWU1 cells. Overexpression of the BmFoxO gene affects cell cycle progression, which results in cell cycle arrest in the G0/G1 phase as well as inhibition of DNA replication. Knockdown of the BmFoxO gene led to cell accumulation at the G2/M phase. The effect of 20E was attenuated after BmFoxO gene knockdown. These findings increase our understanding of the function of 20E in the regulation of the cell cycle in B. mori.

scholarly journals Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by β-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 858 ◽  
Author(s):  
Antonella Di Sotto ◽  
Silvia Di Giacomo ◽  
Elisabetta Rubini ◽  
Alberto Macone ◽  
Marco Gulli ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoints ◽  
Cycle Arrest ◽  
Stat3 Signaling ◽  
Mechanistic Analysis ◽  
M Phase ◽  
A Cell ◽  
Poor Outcomes

Cholangiocarcinoma (CCA) is an aggressive group of biliary tract cancers, characterized by late diagnosis, low effective chemotherapies, multidrug resistance, and poor outcomes. In the attempt to identify new therapeutic strategies for CCA, we studied the antiproliferative activity of a combination between doxorubicin and the natural sesquiterpene β-caryophyllene in cholangiocarcinoma Mz-ChA-1 cells and nonmalignant H69 cholangiocytes, under both long-term and metronomic schedules. The modulation of STAT3 signaling, oxidative stress, DNA damage response, cell cycle progression and apoptosis was investigated as possible mechanisms of action. β-caryophyllene was able to synergize the cytotoxicity of low dose doxorubicin in Mz-ChA-1 cells, while producing cytoprotective effects in H69 cholangiocytes, mainly after a long-term exposure of 24 h. The mechanistic analysis highlighted that the sesquiterpene induced a cell cycle arrest in G2/M phase along with the doxorubicin-induced accumulation in S phase, reduced the γH2AX and GSH levels without affecting GSSG. ROS amount was partly lowered by the combination in Mz-ChA-1 cells, while increased in H69 cells. A lowered expression of doxorubicin-induced STAT3 activation was found in the presence of β-caryophyllene in both cancer and normal cholangiocytes. These networking effects resulted in an increased apoptosis rate in Mz-ChA-1 cells, despite a lowering in H69 cholangiocytes. This evidence highlighted a possible role of STAT3 as a final effector of a complex network regulated by β-caryophyllene, which leads to an enhanced doxorubicin-sensitivity of cholangiocarcinoma cells and a lowered chemotherapy toxicity in nonmalignant cholangiocytes, thus strengthening the interest for this natural sesquiterpene as a dual-acting chemosensitizing and chemopreventive agent.

scholarly journals The Checkpoint Protein Rad24 of Saccharomyces cerevisiae Is Involved in Processing Double-Strand Break Ends and in Recombination Partner Choice

2003 ◽  
Vol 23 (18) ◽  
pp. 6585-6596 ◽  
Author(s):  
Yael Aylon ◽  
Martin Kupiec
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Strand Break ◽  
Double Strand Break ◽  
Partner Choice ◽  
Checkpoint Response ◽  
Checkpoint Protein ◽  
Cycle Arrest ◽  
M Phase ◽  
Kinetics Of

ABSTRACT Upon chromosomal damage, cells activate a checkpoint response that includes cell cycle arrest and a stimulation of DNA repair. The checkpoint protein Rad24 is key to the survival of a single, repairable double-strand break (DSB). However, the low survival of rad24 cells is not due to their inability to arrest cell cycle progression. In rad24 mutants, processing of the broken ends is delayed and protracted, resulting in extended kinetics of DSB repair and in cell death. The limited resection of rad24 mutants also affects recombination partner choice by a mechanism dependent on the length of the interacting homologous donor sequences. Unexpectedly, rad24 cells with a DSB eventually accumulate and die at the G2/M phase of the cell cycle. This arrest depends on the spindle checkpoint protein Mad2.

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