scholarly journals Validation of Enhancing Effects of Curcumin on Radiotherapy with F98/FGT Glioblastoma-Bearing Rat Model

2020 ◽  
Vol 21 (12) ◽  
pp. 4385
Author(s):  
Wei-Hsun Wang ◽  
Chao-Yu Shen ◽  
Yi-Chun Chien ◽  
Wen-Shin Chang ◽  
Chia-Wen Tsai ◽  
...  
Keyword(s):  
Overall Survival ◽  
Animal Model ◽  
Rat Model ◽  
Therapeutic Efficacy ◽  
Lentivirus Vector ◽  
M Cell ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Simultaneous Evaluation

Glioblastoma, the most common and aggressive brain tumor with low survival rate, is difficult to be cured by neurosurgery or radiotherapy. Mounting evidence has reported the anti-inflammatory and anticancer effects of curcumin on several types of cancer in preclinical studies and clinical trials. To our knowledge, there is no platform or system that could be used to effectively and real-timely evaluate the therapeutic efficacy of curcumin for glioblastoma multiforme (GBM). In this study, we constructed a lentivirus vector with triple-reporter genes (Fluc/GFP/tk) and transduced into rat F98 glioblastoma cells to establish an orthotopic F98/FGT glioma-bearing rat model. In the model, the therapeutic efficacies for curcumin alone, radiation alone, and their combination were evaluated via noninvasive bioluminescent imaging and overall survival measurements. At the cell level, curcumin is capable of causing a G2/M cell cycle arrest and sensitizing the F98 cells to radiation. In animal model, curcumin synergistically enhances the effects of radiotherapy on suppressing the growth of both transplanted glioma cells and in situ brain tumors, and extending the overall survival periods longer than those of curcumin alone and radiation alone treatments. In conclusion, we have demonstrated that curcumin may serve as a novel radiosensitizer to combine with radiotherapy using the triple-reporter F98/FGT animal model for effective and simultaneous evaluation of therapeutic efficacy.

scholarly journals Bortezomib Is Effective in Treating T-ALL, Inducting G2/M Cell Cycle Arrest and WEE1 Downregulation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4360-4360
Author(s):  
SIN Chun-fung ◽  
Timothy Ming-hun Wan ◽  
Aarmann Anil Mohinani Mohan ◽  
Yinxia Qiu ◽  
Anan Jiao
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Line ◽  
Cell Lines ◽  
Mechanism Of Action ◽  
Therapeutic Efficacy ◽  
Cyclin B1 ◽  
M Cell ◽  
Cycle Arrest ◽  
Cell Cycle Modulation

Abstract T lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy with poor outcome, especially for relapse/refractory disease. Early T- cell precursor acute lymphoblastic leukaemia (ETP-ALL) is a recently identified subtype of T-ALL with worse treatment outcome compared with other subtypes of T-ALL and treatment options are limited. T-ALL frequently harbors genetic aberrations leading to cell cycle dysregulation and it is one of the major molecular pathogenesis of T-ALL. WEE1 is a protein kinase that is responsible for inhibiting mitosis with unrepaired damaged DNA via inactivating CDK1. WEE1 is highly express in adult T-ALL and its overexpression is associated with adverse prognosis in various cancers. Inhibiting WEE1 expression is a novel approach of therapy. Bortezomib is a 26S proteosome inhibitor and it is FDA approved for treating plasma cell myeloma and mantle cell lymphoma. Bortezomib had been demonstrated therapeutic efficacy in clinical setting for relapse/refractory paediatric T-ALL and B-ALL when combined with chemotherapy. Despite its therapeutic efficacy in clinical studies, the mechanism of action of Bortezomib in T-ALL remain uncertain. The role of Bortezomib in cell cycle modulation had not been established in T-ALL. Moreover, it had not been demonstrated that the effect of Bortezomib in WEE1 expression in T-ALL. Here, we present our study that demonstrated the therapeutic efficacy of Bortezomib in treating T-ALL via cell cycle modulation and downregulation of WEE1 by Bortezomib. T-ALL cell lines including MOLT16, MOLT4, LOUCY and CEM were used in the study. Cell viability was measured by trypan blue. Apoptosis and cell cycle analysis were measured by flow cytometry. Western blot of WEE1, p53, cyclin B1, p21 and p27 were performed. Our result showed that Bortezomib reduce the cell viability of T-ALL cell lines in dose and time-dependent manner. Bortezomib was also sensitive towards LOUCY, a T-ALL cell line with ETP-ALL phenotype. It implied that Bortezomib could be a promising therapy for ETP-ALL. Bortezomib also triggered apoptosis in various T-ALL and the effect of apoptosis was more pronounced after 72 hours of treatment when compared with 24-hour. Again, Bortezomib was able to induce apoptosis in LOUCY cell line. G2/M cell cycle arrest was observed in various T-ALL upon treatment of Bortezomib. The effect on cell cycle modulation was also observed in LOUCY cell line. The protein expression of p21 and p27 were increased after the treatment of Bortezomib. The level of cyclin B1 was increased also. There was upregulation of p53 after Bortezomib treatment. Strikingly, the protein expression level of WEE1 was reduced. The findings of WEE1 downregulation by Bortezomib is a novel findings. We also showed that Bortezomib downregulate WEE1 mRNA expression by quantitative PCR. Our study showed that Bortezomib is active against T-ALL cell lines, including ETP-ALL cell line, LOUCY and modulates cell cycle with G2/M arrest. Bortezomib had been shown to increase the level of p21, p27 and cyclin B1 and induced G2/M cell cycle arrest in glioblastoma cells. However, studies on cell cycle modulation by Bortezomib in T-ALL are scarce. Here, we demonstrated Bortezomib stabilized p21, p27 and upregulation of cyclin B1 in T-ALL as well, which could account for the G2/M cell cycle arrest. We first showed that downregulation of WEE1 after treatment with Bortezomib, in protein level as well as in mRNA level. Recent study showed that inhibition of WEE1 is a novel target of therapy in T-ALL. WEE1 is upregulated in T-ALL to prevent entry of mitosis with unrepaired damaged DNA. The downregulation of WEE1 by Bortezomib as showed by our study could reverse its effect and leads to apoptosis of leukaemic cells. In summary, our study provides the insight on mechanism of action of Bortezomib in modulating cell cycle in T-ALL. Moreover, it is the first study to demonstrate WEE1 downregulation by Bortezomib in T-ALL. These findings not only enhance our understanding of mechanism of action of Bortezomib in T-ALL, but also rationalized the use of certain synergistics combination therapy with Bortezomib in treating T-ALL, e.g., chemotherapeutic agents, PARP inhibitors which could damage DNA of leukaemic cells. Further research is needed to explore those combination therapy in T-ALL and molecular mechanism of downregulation of WEE1 by Bortezomib in T-ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

Deglucohellebrin: A Potent Agent for Glioblastoma Treatment

2020 ◽  
Vol 20 (1) ◽  
pp. 103-110
Author(s):  
Evrysthenis Vartholomatos ◽  
George A. Alexiou ◽  
Georgios S. Markopoulos ◽  
Diamanto Lazari ◽  
Olga Tsiftsoglou ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Primary Brain Tumor ◽  
Behavioral Alterations ◽  
Endemic Plant ◽  
M Cell ◽  
Apoptotic Pathway ◽  
Cycle Arrest ◽  
Dismal Prognosis ◽  
Mitochondrial Membrane Depolarization ◽  
Induced Changes

Background: Glioblastoma is the most common primary brain tumor in adults with a dismal prognosis. To date, several anticancer agents have been isolated from plants. Helleborus odorus subsp. Cyclophyllus is an endemic plant of the Balcan flora. Herewith, we investigated for the first time, the anti-glioma effect of deglucohellebrin (DGH) extracted from the roots of Helleborus. Methods: We investigated the effect of DGH in U251MG, T98G and U87G glioblastoma cell lines. We selected the T98G cells because of their inherent temozolomide resistance. Results: The IC50 value of reduced viability for DGH was 7x10-5M in U251MG cells, 5x10-5M for the T98G cells and 4x10-5M in U87G cells during 72h treatment. DGH induced G2/M cell cycle arrest, caspace-8 activation and significant mitochondrial membrane depolarization, suggesting the activation of the intrinsic, mitochondrial- dependent apoptotic pathway. DGH and temozolomide induced changes in CDs’ expression in U251MG and T98G cells. In zebrafish, DGH did not induce toxicity or behavioral alterations. Conclusion: The present study is the first to determine the anti-glioma activity of DGH. DGH may be a potent agent for glioblastoma treatment and further studies are needed.

scholarly journals A Potent HDAC Inhibitor, 1-Alaninechlamydocin, from aTolypocladiumsp. Induces G2/M Cell Cycle Arrest and Apoptosis in MIA PaCa-2 Cells

2014 ◽  
Vol 77 (7) ◽  
pp. 1753-1757 ◽  
Author(s):  
Lin Du ◽  
April L. Risinger ◽  
Jarrod B. King ◽  
Douglas R. Powell ◽  
Robert H. Cichewicz
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Hdac Inhibitor ◽  
M Cell ◽  
Cycle Arrest
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