Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide

2003 ◽  
Vol 99 (6) ◽  
pp. 1047-1052 ◽  
Author(s):  
Takao Kanzawa ◽  
Joshua Bedwell ◽  
Yasuko Kondo ◽  
Seiji Kondo ◽  
Isabelle M. Germano
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Cell Viability ◽  
Cell Cycle Arrest ◽  
Glioma Cells ◽  
Glioblastoma Cell ◽  
Content Type ◽  
Cycle Arrest ◽  
M Phase ◽  
Fine Print

Object. Temozolomide (TMZ) is a DNA alkylating agent currently used as adjuvant treatment for anaplastic astrocytomas. Its use in managing glioblastoma multiforme has been halted because of the lack of therapeutic effects due to cell resistance. Note that O6-alkylguanine—DNA alkyltranferase (AGT) is a DNA repair enzyme that limits the efficacy of TMZ. In this study the authors investigated the ability of O6-benzylguanine (BG), an AGT inhibitor, to sensitize a glioblastoma cell line resistant to TMZ. Methods. The effects of TMZ alone (100 µg) and after exposure to BG (50 µg) were assessed in two glioblastoma cell lines, U373-MG and T98G, respectively, sensitive and resistant to TMZ. Cell viability was assessed using trypan blue; cell cycle analysis by fluorescence-activated cell sorter; and apoptosis and autophagy by terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and acridine orange staining, respectively. Furthermore, the involvement of an autophagy marker, microtubule-associated light chain 3 (LC3), was assessed. Temozolomide suppressed the growth of and caused cell cycle arrest in the G2—M phase of U373-MG cells but not T98G cells. Exposure to BG prior to TMZ resulted in a significant decrease in cell viability as well as cell cycle arrest in the G2—M phase in T98G cells (p < 0.05). Although apoptosis was not detected on TUNEL staining, programmed cell death Type II (autophagy) was detected after exposure to BG and TMZ in T98G cells. Conclusions. These results indicate that inhibition of AGT by BG can render previously resistant glioma cells sensitive to TMZ treatment. The mechanism of cell demise following BG-TMZ treatment seems to be autophagy and not apoptosis. Combination therapy involving TMZ and an AGT inhibitor may be an effective strategy to treat resistant gliomas.

Molecular response of human glioblastoma multiforme cells to ionizing radiation: cell cycle arrest, modulation of cyclin-dependent kinase inhibitors, and autophagy

2003 ◽  
Vol 98 (2) ◽  
pp. 378-384 ◽  
Author(s):  
Kevin C. Yao ◽  
Tadashi Komata ◽  
Yasuko Kondo ◽  
Takao Kanzawa ◽  
Seiji Kondo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Glioblastoma Multiforme ◽  
Ionizing Radiation ◽  
Cell Cycle Arrest ◽  
Cell Line ◽  
Kinase Inhibitors ◽  
Cyclin Dependent Kinase ◽  
Content Type ◽  
Cycle Arrest ◽  
Fine Print

Object. Ionizing radiation is the gold-standard adjuvant treatment for glioblastoma multiforme (GBM), the most aggressive primary brain tumor. The mechanisms underlying neoplastic glial cell growth inhibition after administration of ionizing radiation, however, remain largely unknown. In this report, the authors characterize the response of GBM cells to ionizing radiation and elucidate factors that correlate with the radiosensitivity of these tumors. Methods. Six human GBM cell lines were subjected to increasing doses of radiation. Each demonstrated a dose-dependent suppression of cell proliferation. In the most radiosensitive cell line, the authors demonstrated a transient increase in the expression of the cyclin-dependent kinase inhibitors (CDKIs) p21 and p27, which corresponded with a G1 cell-cycle arrest. In contrast, the most radioresistant cell line demonstrated a decrease in p21 and p27 expression levels, which correlated with a failure to arrest. Apoptosis did not occur in any cell line following irradiation. Instead, autophagic cell changes were observed following administration of radiation, regardless of the relative radiosensitivity of the cell line. Conclusions. These findings elucidate some of the molecular responses of GBMs to irradiation and suggest novel targets for future therapy.

scholarly journals PDPN Is Expressed in Various Types of Canine Tumors and Its Silencing Induces Apoptosis and Cell Cycle Arrest in Canine Malignant Melanoma

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1136 ◽  
Author(s):  
Masahiro Shinada ◽  
Daiki Kato ◽  
Satoshi Kamoto ◽  
Sho Yoshimoto ◽  
Masaya Tsuboi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Malignant Melanoma ◽  
Cell Viability ◽  
Cell Cycle Arrest ◽  
Phase Cell ◽  
Cancer Stemness ◽  
Cycle Arrest ◽  
M Phase ◽  
Canine Tumors ◽  
Induction Of Apoptosis

Podoplanin (PDPN), a small transmembrane mucin-like glycoprotein, is ectopically expressed. It is also known to be linked with several aspects of tumor malignancy in some types of human tumors, including invasion, metastasis, and cancer stemness. However, there are few reports on the expression of dog PDPN (dPDPN) in canine tumors, and the association between dPDPN and tumor malignancy has not been elucidated. We identified that 11 out of 18 types of canine tumors expressed dPDPN. Furthermore, 80% of canine malignant melanoma (MM), squamous cell carcinoma, and meningioma expressed dPDPN. Moreover, the expression density of dPDPN was positively associated with the expression of the Ki67 proliferation marker. The silencing of dPDPN by siRNAs resulted in the suppression of cell migration, invasion, stem cell-like characteristics, and cell viability in canine MM cell lines. The suppression of cell viability was caused by the induction of apoptosis and G2/M phase cell cycle arrest. Overall, this study demonstrates that dPDPN is expressed in various types of canine tumors and that dPDPN silencing suppresses cell viability through apoptosis and cell cycle arrest, thus providing a novel biological role for PDPN in tumor progression.

Abstract 1670: Radiosensitization of glioma cells by the ketone body β-hydroxybutyrate is associated with enhanced cell cycle arrest in the G2/M phase

2016 ◽  
Author(s):  
Helena B. Silva-Nichols ◽  
Alex P. Rossi ◽  
Eric C. Woolf ◽  
Marshall J. Fairres ◽  
Loic P. Deleyrolle ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Ketone Body ◽  
Glioma Cells ◽  
Cycle Arrest ◽  
M Phase

scholarly journals Allicin suppresses human glioblastoma cell growth by inducing cell cycle arrest and apoptosis, and by promoting autophagy

2020 ◽  
Vol 72 (3) ◽  
pp. 313-319
Author(s):  
Oratai Weeranantanapan ◽  
Kankawi Satsantitham ◽  
Pishyaporn Sritangos ◽  
Nuannoi Chudapongse
Keyword(s):  
Cell Cycle ◽  
Cell Migration ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Phase Cell ◽  
Glioblastoma Cell ◽  
Human Glioblastoma ◽  
Human Glioblastoma Cell ◽  
Cycle Arrest ◽  
M Phase

Glioblastoma is the most aggressive cancer that occurs in the brain and spinal cord. In the present study, we investigated the effect of allicin, an organosulfur compound obtained from garlic (Allium sativum), on glioblastoma cell growth. When human glioblastoma DBTRG-05MG cells were incubated with different concentrations of allicin for 24 h, cell growth was suppressed in a dose-dependent manner. The results from image-based cytometer assays suggested that allicin caused S and G2/M phase cell cycle arrest and induced apoptosis. Autophagy detection studies showed that allicin also promoted this mechanism. Because cell migration is a key process during tumor formation, the effect of allicin on glioblastoma cell migration was also examined. After allicin treatment, the migration ability of cells decreased when compared with the control after 24 h. Taken together, the present results suggested that allicin inhibited human glioblastoma cell growth by inducing S and G2/M phase cell cycle arrest, apoptosis and autophagy. Our findings suggest that allicin suppressed glioblastoma cell growth through multiple target pathways. Therefore, allicin potentially serves as an alternative therapeutic candidate or could be synergistically used in combination with the standard drug for the treatment of glioblastoma multiforme.

scholarly journals miR‑138‑5p suppresses glioblastoma cell viability and leads to cell cycle arrest by targeting cyclin D3

2020 ◽  
Vol 20 (5) ◽  
pp. 1-1
Author(s):  
Henggang Wu ◽  
Cheng Wang ◽  
Yajun Liu ◽  
Chao Yang ◽  
Xiaolong Liang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Cell Cycle Arrest ◽  
Glioblastoma Cell ◽  
Cycle Arrest

MicroRNA-490-5P Targets CCND1 to Suppress Cellular Proliferation in Glioma Cells and Tissue Through Cell Cycle Arrest

2018 ◽  
Vol 15 (3) ◽  
pp. 246-255 ◽  
Author(s):  
Long Zhao ◽  
Xiaoping Tang ◽  
Renguo Luo ◽  
Jie Duan ◽  
Yuanchuan Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Proliferation ◽  
Glioma Cells ◽  
Cycle Arrest

Pisosterol Induces G2/M Cell Cycle Arrest and Apoptosis via the ATM/ATR Signaling Pathway in Human Glioma Cells

2020 ◽  
Vol 20 (6) ◽  
pp. 734-750
Author(s):  
Wallax A.S. Ferreira ◽  
Rommel R. Burbano ◽  
Claudia do Ó. Pessoa ◽  
Maria L. Harada ◽  
Bárbara do Nascimento Borges ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Glioma Cell ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Dependent Manner ◽  
M Cell ◽  
Trypan Blue Exclusion ◽  
Cycle Arrest

Background: Pisosterol, a triterpene derived from Pisolithus tinctorius, exhibits potential antitumor activity in various malignancies. However, the molecular mechanisms that mediate the pisosterol-specific effects on glioma cells remain unknown. Objective: This study aimed to evaluate the antitumoral effects of pisosterol on glioma cell lines. Methods: The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue exclusion assays were used to evaluate the effect of pisosterol on cell proliferation and viability in glioma cells. The effect of pisosterol on the distribution of the cells in the cell cycle was performed by flow cytometry. The expression and methylation pattern of the promoter region of MYC, ATM, BCL2, BMI1, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, MDM2, p14ARF and TP53 was analyzed by RT-qPCR, western blotting and bisulfite sequencing PCR (BSP-PCR). Results: Here, it has been reported that pisosterol markedly induced G2/M arrest and apoptosis and decreased the cell viability and proliferation potential of glioma cells in a dose-dependent manner by increasing the expression of ATM, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, p14ARF and TP53 and decreasing the expression of MYC, BCL2, BMI1 and MDM2. Pisosterol also triggered both caspase-independent and caspase-dependent apoptotic pathways by regulating the expression of Bcl-2 and activating caspase-3 and p53. Conclusions: It has been, for the first time, confirmed that the ATM/ATR signaling pathway is a critical mechanism for G2/M arrest in pisosterol-induced glioma cell cycle arrest and suggests that this compound might be a promising anticancer candidate for further investigation.

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.

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