scholarly journals CDK4/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms

2020 ◽  
Vol 123 (3) ◽  
pp. 378-391 ◽  
Author(s):  
Margaretha A. Skowron ◽  
Marieke Vermeulen ◽  
Anna Winkelhausen ◽  
Teresa K. Becker ◽  
Felix Bremmer ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Germ Cell ◽  
Cell Cycle Arrest ◽  
Therapeutic Option ◽  
Germ Cell Tumours ◽  
Cycle Arrest

scholarly journals Targeting Germ Cell Tumors with the Newly Synthesized Flavanone-Derived Compound MLo1302 Efficiently Reduces Tumor Cell Viability and Induces Apoptosis and Cell Cycle Arrest

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 73
Author(s):  
João Lobo ◽  
Ana Rita Cardoso ◽  
Vera Miranda-Gonçalves ◽  
Leendert H. J. Looijenga ◽  
Marie Lopez ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Expression ◽  
Cell Viability ◽  
Germ Cell ◽  
Cell Cycle Arrest ◽  
Dna Methyltransferase ◽  
Germ Cell Tumors ◽  
Flavonoid Compound ◽  
Testicular Germ Cell ◽  
Cycle Arrest

Less toxic treatment strategies for testicular germ cell tumor (TGCT) patients are needed, as overtreatment is a concern due to the long-term side effects of platin-based chemotherapy. Although clinical benefit from classical hypomethylating agents has to date been limited, TGCTs show an abnormal DNA methylome indicating the potential of treating TGCTs with hypomethylating drugs. We tested, for the first time in TGCT cell lines, a new synthetic flavonoid compound (MLo1302) from the 3-nitroflavanone family of DNA methyltransferase (DNMT) inhibitors. We show that MLo1302 reduces cell viability (including of cisplatin resistant cell line NCCIT-R), with IC50s (inhibitory concentration 50) within the nanomolar range for NCCIT and NTERA-2 cells, and proved its cytotoxic effect. Exposure to MLo1302 reduced DNMT protein expression, similar to decitabine, and showed a partial effect in cell differentiation, reducing protein expression of pluripotency markers. RT2 profiler expression array indicated several dysregulated targets, related to activation of apoptosis, differentiation, and cell cycle arrest. We validated these data by showing increased apoptosis, increased protein expression of cleaved caspase 8 and activated caspase 2, and reduced proliferation (BrdU assay), with increase in CDKN1A and decrease in MIB-1 expression. Therefore, synthetic drugs designed to target DNA methylation in cells may uncover effective treatments for TGCT patients.

scholarly journals Secretome analysis of patient-derived GBM tumor spheres identifies midkine as a potent therapeutic target

2019 ◽  
Vol 51 (12) ◽  
pp. 1-11 ◽  
Author(s):  
Suji Han ◽  
Hyemi Shin ◽  
Jin-Ku Lee ◽  
Zhaoqi Liu ◽  
Raul Rabadan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Apoptotic Cell ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Antitumor Effects ◽  
Promote Cell Proliferation ◽  
Cycle Arrest ◽  
Autocrine Factor

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of glioma-initiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis.

scholarly journals Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background

Development ◽  
2010 ◽  
Vol 138 (1) ◽  
pp. 23-32 ◽  
Author(s):  
M. S. Cook ◽  
S. C. Munger ◽  
J. H. Nadeau ◽  
B. Capel
Keyword(s):  
Cell Cycle ◽  
Germ Cell ◽  
Cell Cycle Arrest ◽  
Genetic Background ◽  
Male Germ Cell ◽  
Cycle Arrest

scholarly journals Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background

2010 ◽  
Vol 124 (1) ◽  
pp. e1-e1 ◽  
Author(s):  
M. S. Cook ◽  
S. C. Munger ◽  
J. H. Nadeau ◽  
B. Capel
Keyword(s):  
Cell Cycle ◽  
Germ Cell ◽  
Cell Cycle Arrest ◽  
Genetic Background ◽  
Male Germ Cell ◽  
Cycle Arrest

Induction of apoptosis by flavopiridol unrelated to cell cycle arrest in germ cell tumour derived cell lines

2005 ◽  
Vol 23 (3) ◽  
pp. 205-211 ◽  
Author(s):  
Frank Mayer ◽  
Sandra Mueller ◽  
Elke Malenke ◽  
M. Kuczyk ◽  
Jörg T. Hartmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Germ Cell ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Germ Cell Tumour ◽  
Cell Tumour ◽  
Cycle Arrest ◽  
Induction Of Apoptosis

scholarly journals Artemisinin triggers induction of cell-cycle arrest and apoptosis in Leishmania donovani promastigotes

2007 ◽  
Vol 56 (9) ◽  
pp. 1213-1218 ◽  
Author(s):  
Rupashree Sen ◽  
Samiran Bandyopadhyay ◽  
Avijit Dutta ◽  
Goutam Mandal ◽  
Sudipto Ganguly ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Leishmania Donovani ◽  
Artemisia Annua ◽  
Therapeutic Option ◽  
Safety Index ◽  
Cycle Arrest ◽  
Major Impediment ◽  
Sodium Antimony Gluconate

A major impediment to effective anti-leishmanial chemotherapy is the emergence of drug resistance, especially to sodium antimony gluconate, the first-line treatment for leishmaniasis. Artemisinin, a sesquiterpene lactone isolated from Artemisia annua, is an established anti-malarial compound that showed anti-leishmanial activity in both promastigotes and amastigotes, with IC50 values of 160 and 22 μM, respectively, and, importantly, was accompanied by a high safety index (>22-fold). The leishmanicidal activity of artemisinin was mediated via apoptosis as evidenced by externalization of phosphatidylserine, loss of mitochondrial membrane potential, in situ labelling of DNA fragments by terminal deoxyribonucleotidyltransferase-mediated dUTP nick end labelling (TUNEL) and cell-cycle arrest at the sub-G0/G1 phase. Taken together, these data indicate that artemisinin has promising anti-leishmanial activity that is mediated by programmed cell death and, accordingly, merits consideration and further investigation as a therapeutic option for the treatment of leishmaniasis.

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