Mollugin induced oxidative DNA damage via up-regulating ROS that caused cell cycle arrest in hepatoma cells

Abstract Prometryn is a slightly to moderately toxic herbicide belonging to the triazine family of herbicides, which are widely used in agriculture to control the growth of various weeds. Although many studies have shown that triazine herbicides have carcinogenic potential in humans, the cytotoxic effects of prometryn on human cells, and the mechanisms underlying these effects, are not yet fully understood. The lung is one of the most important organs where there is accumulation of environmental pollutants. The aim of this study was to determine the cytotoxic effects of prometryn on normal lung cells using the human bronchial epithelial cell line BEAS-2B. We found that treatment with high concentrations of prometryn arrested BEAS-2B cell growth in the S phase, while at low concentrations the cell cycle was not affected. Furthermore, we observed changes in the expression levels of cyclin-dependent kinase 2 (CDK2) and cyclin A that were consistent with the induction of cell cycle arrest in BEAS-2B cells exposed to prometryn. We also observed the increased formation of intracellular reactive oxygen species (ROS) in BEAS-2B cells, suggesting that this cell line is sensitive to prometryn. Finally, prometryn induced DNA double-strand breaks in BEAS-2B cells. In conclusion, prometryn affected key molecules involved in cell cycle regulation, induced oxidative stress, and induced DNA damage in BEAS-2B cells, which may shed light on the mechanism by which prometryn promotes lung cancer development.

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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 ◽

10.3390/molecules25030501 ◽

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.

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Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction

Molecules ◽

10.3390/molecules26051453 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1453

Author(s):

Haoran Wang ◽

Jianhua Wei ◽

Hong Jiang ◽

Ye Zhang ◽

Caina Jiang ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Antitumor Agents ◽

Mechanistic Study ◽

Ros Generation ◽

Polypyridyl Complexes ◽

Expression Levels ◽

Cycle Arrest ◽

Study Results

The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (6a–6c) were synthesized as antitumor agents. Compounds 6a and 6c exhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly, 6a effectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of 6a and 6c, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that 6a and 6c arrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition, 6a and 6c caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca2+ release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that 6a and 6c exerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.

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ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)84970-9 ◽

2002 ◽

Vol 277 (23) ◽

pp. 21110 ◽

Cited By ~ 1

Author(s):

Damu Tang ◽

Dongcheng Wu ◽

Atsushi Hirao ◽

Jill M. Lahti ◽

Lieqi Liu ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Erk Activation ◽

Cycle Arrest

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P28-10 Cisplatin induces DNA damage associated with cell cycle arrest and apoptosis in PC9 cells

Annals of Oncology ◽

10.1016/j.annonc.2021.05.736 ◽

2021 ◽

Vol 32 ◽

pp. S346

Author(s):

Md Mohiuddin ◽

Hideharu Kimura ◽

Takashi Sone ◽

Hiroki Matsuoka ◽

Keigo Saeki ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cycle Arrest

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Aqueous Extracts of the Edible Gracilaria tenuistipitata are Protective Against H2O2-Induced DNA Damage, Growth Inhibition, and Cell Cycle Arrest

Molecules ◽

10.3390/molecules17067241 ◽

2012 ◽

Vol 17 (6) ◽

pp. 7241-7254 ◽

Cited By ~ 38

Author(s):

Jing-Iong Yang ◽

Chi-Chen Yeh ◽

Jin-Ching Lee ◽

Szu-Cheng Yi ◽

Hurng-Wern Huang ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Growth Inhibition ◽

Cell Cycle Arrest ◽

Aqueous Extracts ◽

Damage Growth ◽

Gracilaria Tenuistipitata ◽

Cycle Arrest

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Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

Chemotherapy ◽

10.1159/000491705 ◽

2018 ◽

Vol 63 (4) ◽

pp. 225-237 ◽

Cited By ~ 1

Author(s):

Haytham Khoury ◽

Ruijuan He ◽

Aaron Schimmer ◽

James R. Beadle ◽

Karl Y. Hostetler ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Acute Myeloid Leukemia ◽

Cell Cycle Arrest ◽

Clinical Benefit ◽

Myeloid Leukemia ◽

Mouse Bone Marrow ◽

Medical Needs ◽

Cycle Arrest ◽

Acute Myeloid

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50–70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipivoxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

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