scholarly journals Histone deacetylase inhibitors vorinostat and panobinostat induce G1 cell cycle arrest and apoptosis in multidrug resistant sarcoma cell lines

Oncotarget ◽  
2017 ◽  
Vol 8 (44) ◽  
pp. 77254-77267 ◽  
Author(s):  
Eva Bernhart ◽  
Nicole Stuendl ◽  
Heike Kaltenegger ◽  
Christian Windpassinger ◽  
Nicholas Donohue ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Histone Deacetylase Inhibitors ◽  
Multidrug Resistant ◽  
Sarcoma Cell ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

scholarly journals Invasive Cell Fate Requires G1 Cell-Cycle Arrest and Histone Deacetylase-Mediated Changes in Gene Expression

2015 ◽  
Vol 35 (2) ◽  
pp. 162-174 ◽  
Author(s):  
David Q. Matus ◽  
Lauren L. Lohmer ◽  
Laura C. Kelley ◽  
Adam J. Schindler ◽  
Abraham Q. Kohrman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Histone Deacetylase ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Invasive Cell

scholarly journals Histone Deacetylase Inhibitors: A Promising Therapeutic Alternative for Endometrial Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Iason Psilopatis ◽  
Alexandros Pergaris ◽  
Constantinos Giaginis ◽  
Stamatios Theocharis
Keyword(s):  
Cell Cycle ◽  
Endometrial Cancer ◽  
Endometrial Carcinoma ◽  
Histone Acetylation ◽  
Cell Cycle Arrest ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
The United States ◽  
Carcinoma Cells ◽  
Cycle Arrest

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Epigenetic alterations are implicated in endometrial cancer development and progression. Histone deacetylase inhibitors are a novel class of anticancer drugs that increase the level of histone acetylation in many cell types, thereby inducing cell cycle arrest, differentiation, and apoptotic cell death. This review is aimed at determining the role of histone acetylation and examining the therapeutic potential of histone deacetylase inhibitors in endometrial cancer. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms histone deacetylase, histone deacetylase inhibitor, and endometrial cancer were employed, and we were able to identify fifty-two studies focused on endometrial carcinoma and published between 2001 and 2021. Deregulation of histone acetylation is involved in the tumorigenesis of both endometrial carcinoma histological types and accounts for high-grade, aggressive carcinomas with worse prognosis and decreased overall survival. Histone deacetylase inhibitors inhibit tumor growth, enhance the transcription of silenced physiologic genes, and induce cell cycle arrest and apoptosis in endometrial carcinoma cells both in vitro and in vivo. The combination of histone deacetylase inhibitors with traditional chemotherapeutic agents shows synergistic cytotoxic effects in endometrial carcinoma cells. Histone acetylation plays an important role in endometrial carcinoma development and progression. Histone deacetylase inhibitors show potent antitumor effects in various endometrial cancer cell lines as well as tumor xenograft models. Additional clinical trials are however needed to verify the clinical utility and safety of these promising therapeutic agents in the treatment of patients with endometrial cancer.

Mechanisms of Sensitivity and Resistance to Histone Deacetylase Inhibitors in Diffuse Large B-Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1359-1359
Author(s):  
Ana A Tula-Sanchez ◽  
Aaron Havas ◽  
Peter Alonge ◽  
Mary E Klein ◽  
Taralyn Y Rogers ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Histone Deacetylase Inhibitors ◽  
B Cell Lymphoma ◽  
Resistant Cell ◽  
G1 Arrest ◽  
Cycle Arrest

Abstract Abstract 1359 Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin Lymphoma (NHL) throughout the world. DLBCL is an aggressive, heterogeneous disease with two major recognized cell-of-origin subtypes: “germinal center” (GCB) and “activated B-cell like” (ABC), the latter having the worse prognosis. Overall, DLBCL remains fatal for about 30% patients due to relapse or lack of response to initial therapy. Resistant/relapsed DLBCL patients could benefit from the addition of new promising antiproliferative drugs, such as histone deacetylase inhibitors (HDACIs), to current chemotherapy regimens. So far, Vorinostat and Romidepsin, two structurally different HDACIs, have been approved for the treatment of hematological cancers. Despite their proven antiproliferative, pro-apoptotic effects, response to these drugs against DLBCL in clinical trials have been variable, ranging from complete/partial responses to stable disease to no response. The mechanisms of action of these drugs are still poorly understood, mainly because the function of their target deacetylases are cell context-specific. Therefore, characterization of the specific anticancer mechanisms of action of HDACIs in DLBCL could potentially lead to development of novel combinatorial drug regimens effective against resistant/relapsed DLBCL patients. To define HDACI action in DLBCL, we treated DLBCL-derived cell lines with PXD101, (Belinostat); a hydroxamate HDACI, like Vorinostat. We demonstrated that PXD101 is able to produce 24h growth inhibition (IC50) at submicromolar concentrations regardless of the DLBCL subtype. The 24h IC50values were used in all the subsequent experiments. Cell cycle and apoptosis analysis by flow cytometry indicated that PXD101 produces cytotoxic effects on two of the GCB cell lines; DB and OCILY19 underwent G2/M cell cycle arrest at 24 hours followed by apoptosis at 48 and 72 hours of treatment. Immunoblotting of PARP and caspase-3 cleavage further confirmed apoptosis. More importantly, when cells were treated for only 8 hours with PXD101 and then the drug was removed for 24 hours, cells showed apoptosis rates similar to those observed with 48h of continuous treatment; suggesting that once that these cell lines are exposed to the drug they rapidly commit to cell death. Thus, we have classified the DB and OCILY19 cell lines as models for sensitivity to the apoptotic effects of HDACI. In contrast, PXD101 induced cytostatic effects on the GCB cell line SUDHL4 and ABC cell lines U2932 and SUDHL8. All three cell lines showed G1 phase cell cycle arrest with little apoptosis. The G1 arrest is reversible after 48 hours of drug removal. Because of the lack of cell death and the reversibility of cell cycle arrest, we have classified these cell lines as models of HDACI resistance. Previous studies have shown that induction of p21 is responsible for G1 arrest in cells treated with HDACIs. Western blot analysis showed that none of the cell lines, except U2932, express p21, but upon PXD101, p21 protein levels were induced at 24, 48 and 72 hours of PXD101 treatment in SUDHL4 and U2932. In contrast, p21 was induced to a lesser extent in OCILY19 and DB, but its expression was not sustained beyond 24 hours of treatment. Since we also observed a corresponding loss in Rb phosphorylation, we tested the effect of PXD101 on cyclin dependent kinase 2 (CDK2) activity. This enzyme complex is responsible for entry into S phase and is inhibited by association with p21. In all three resistant cell lines CDK2 activity was reduced after only 24 hours of treatment with PXD101. The loss in activity was correlated with increased association with p21, as determined by immunoprecipitation. These results indicate that sustained upregulation of p21 by HDACIs such as PXD101 plays a role in bringing about G1 arrest that may protect DLBCL cells from apoptosis. Combined treatment with therapeutics that prevent p21 upregulation and G1 arrest may work synergistically with HDACIs to trigger apoptosis in HDACI-resistant cell lines. To that end, we have begun analysis of the cyclin-dependent kinase inhibitor, flavopiridol, and have shown that it prevents both p21 upregulation and G1 arrest in the HDACi-resistant DLBCL cell lines. Studies to measure synergism with PXD101 in bringing about cell death are currently underway. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Combined paclitaxel, cisplatin and fluorouracil therapy enhances ionizing radiation effects, inhibits migration and induces G0/G1 cell cycle arrest and apoptosis in oral carcinoma cell lines

2015 ◽  
Vol 10 (3) ◽  
pp. 1721-1727 ◽  
Author(s):  
SILVIA TAVEIRA ELIAS ◽  
GABRIEL ALVARES BORGES ◽  
DANIELA FORTUNATO RÊGO ◽  
LUIS FELIPE OLIVEIRA E SILVA ◽  
SAMUEL AVELINO ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ionizing Radiation ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Radiation Effects ◽  
Carcinoma Cell ◽  
Oral Carcinoma ◽  
Cycle Arrest ◽  
Carcinoma Cell Lines ◽  
G1 Cell Cycle Arrest

scholarly journals Trichodermin Induces G0/G1 Cell Cycle Arrest by Inhibiting c-Myc in Ovarian Cancer Cells and Tumor Xenograft-Bearing Mice

2021 ◽  
Vol 22 (9) ◽  
pp. 5022
Author(s):  
Ying Gao ◽  
Sarah L. Miles ◽  
Piyali Dasgupta ◽  
Gary O. Rankin ◽  
Stephen Cutler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Ovarian Cancer Cells ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Ovarian cancer is a fatal gynecological cancer because of a lack of early diagnosis, which often relapses as chemoresistant. Trichodermin, a trichothecene first isolated from Trichoderma viride, is an inhibitor of eukaryotic protein synthesis. However, whether trichodermin is able to suppress ovarian cancer or not was unclear. In this study, trichodermin (0.5 µM or greater) significantly decreased the proliferation of two ovarian cancer cell lines A2780/CP70 and OVCAR-3. Normal ovarian IOSE 346 cells were much less susceptible to trichodermin than the cancer cell lines. Trichodermin predominantly inhibited ovarian cancer cells by inducing G0/G1 cell cycle arrest rather than apoptosis. Trichodermin decreased the expression of cyclin D1, CDK4, CDK2, retinoblastoma protein, Cdc25A, and c-Myc but showed little effect on the expression of p21Waf1/Cip1, p27Kip1, or p16Ink4a. c-Myc was a key target of trichodermin. Trichodermin regulated the expression of Cdc25A and its downstream proteins via c-Myc. Overexpression of c-Myc attenuated trichodermin’s anti-ovarian cancer activity. In addition, trichodermin decelerated tumor growth in BALB/c nude mice, proving its effectiveness in vivo. These findings suggested that trichodermin has the potential to contribute to the treatment of ovarian cancer.

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