scholarly journals Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Haruna Ebisu ◽  
Kana Shintani ◽  
Takumi Chinen ◽  
Yoko Nagumo ◽  
Shuya Shioda ◽  
...  
Keyword(s):  
Cell Death ◽  
Side Effects ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Combined Treatment ◽  
Specific Inhibitor ◽  
Mitotic Cell ◽  
Tubulin Inhibitor ◽  
Tubulin Inhibitors ◽  
Bi 2536

α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor. The cytotoxicity of gatastatin was relatively weak compared with that of the conventional MT inhibitors, paclitaxel and vinblastine. To improve the cytotoxicity, we screened the chemicals that improve the effects of gatastatin and found that BI 2536, a Plk1 inhibitor, greatly increases the cytotoxicity of gatastatin. Co-treatment with gatastatin and BI 2536 arrested cell cycle progression at mitosis with abnormal spindles. Moreover, mitotic cell death induced by the combined treatment was suppressed by the Mps1 inhibitor, reversine. These findings suggest that co-treatment with Plk1 and γ-tubulin inhibitors causes spindle assembly checkpoint-dependent mitotic cell death by impairing centrosome functions. These results raise the possibility of Plk1 and γ-tubulin inhibitor co-treatment as a novel cancer chemotherapy.

scholarly journals Delayed Cell Cycle Progression and Apoptosis Induced by Hemicellulase-TreatedAgaricus blazei

2007 ◽  
Vol 4 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Masaki Kawamura ◽  
Hirotake Kasai
Keyword(s):  
Cell Cycle ◽  
P38 Mapk ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Combined Treatment ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Activation Effect ◽  
Cycle Progression ◽  
Fraction H

We examined the effects of hemicellulase-treatedAgaricus blazei(AB fraction H, ABH) on growth of several tumor cell lines. ABH inhibited the proliferation of some cell lines without cytotoxic effects. It markedly prolonged the S phase of the cell cycle. ABH also induced mitochondria-mediated apoptosis in different cell lines. However, it had no impact on the growth of other cell lines. ABH induced strong activation of p38 mitogen-activated protein kinase (MAPK) in the cells in which it evoked apoptosis. On the other hand, ABH showed only a weak p38 activation effect in those cell lines in which it delayed cell cycle progression with little induction of apoptosis. However, p38 MAPK-specific inhibitor inhibited both ABH-induced effects, and ABH also caused apoptosis in the latter cells under conditions of high p38 MAPK activity induced by combined treatment with TNF-α. These results indicate that the responsiveness of p38 MAPK to ABH, which differs between cell lines, determines subsequent cellular responses on cell growth.

scholarly journals Consequences of mitotic slippage for antimicrotubule drug therapy

2017 ◽  
Vol 24 (9) ◽  
pp. T97-T106 ◽  
Author(s):  
Bing Cheng ◽  
Karen Crasta
Keyword(s):  
Cell Death ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Cell ◽  
G1 Arrest ◽  
Front Line ◽  
Cell Fates ◽  
Mitotic Slippage ◽  
Drug Treatment Outcomes ◽  
Antimicrotubule Agents ◽  
Sustained Activation

Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage. Here, mitotically arrested cells ‘slip’ to the next interphase without undergoing proper chromosome segregation and cytokinesis. These post-slippage cells in turn have two main cell fates, either cell death or a G1 arrest ensuing in senescence. In this review, we take a look at the factors determining mitotic cell death vs mitotic slippage, post-slippage cell fates and accompanying features, and their consequences for antimicrotubule drug treatment outcomes.

scholarly journals Inhibition of Drp1 Sensitizes Cancer Cells to Cisplatin-Induced Apoptosis through Transcriptional Inhibition of c-FLIP Expression

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5793
Author(s):  
Seon Min Woo ◽  
Kyoung-jin Min ◽  
Taeg Kyu Kwon
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Apoptotic Cell Death ◽  
Induced Apoptosis

Mitochondrial fragmentation occurs during the apoptosis. Dynamin-related protein 1 (Drp1) acts as an important component in mitochondrial fission machinery and can regulate various biological processes including apoptosis, cell cycle, and proliferation. The present study demonstrates that dysfunction of mitochondrial dynamics plays a pivotal role in cisplatin-induced apoptosis. Inhibiting the mitochondrial fission with the specific inhibitor (Mdivi-1) did not affect apoptotic cell death in low concentrations (<10 μM). Interestingly, mdivi-1 enhanced cisplatin-induced apoptosis in cancer cells, but not in normal cells. Particularly in the presence of mdivi-1, several human cancer cell lines, including renal carcinoma cell line Caki-1, became vulnerable to cisplatin by demonstrating the traits of caspase 3-dependent apoptosis. Combined treatment induced downregulation of c-FLIP expression transcriptionally, and ectopic expression of c-FLIP attenuated combined treatment-induced apoptotic cell death with mdivi-1 plus cisplatin. Collectively, our data provide evidence that mdivi-1 might be a cisplatin sensitizer.

scholarly journals THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death

2009 ◽  
Vol 297 (2) ◽  
pp. H643-H653 ◽  
Author(s):  
Meenakshi P. Balakrishnan ◽  
Lucia Cilenti ◽  
Zineb Mashak ◽  
Paiyal Popat ◽  
Emad S. Alnemri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Human Heart ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Specific Inhibitor ◽  
Dual Function ◽  
Protein Levels ◽  
Cycle Arrest ◽  
Artery Disease

Omi/HtrA2 is a mitochondrial serine protease that has a dual function: while confined in the mitochondria, it promotes cell survival, but when released into the cytoplasm, it participates in caspase-dependent as well as caspase-independent cell death. To investigate the mechanism of Omi/HtrA2's function, we set out to isolate and characterize novel substrates for this protease. We have identified Thanatos-associated protein 5 (THAP5) as a specific interactor and substrate of Omi/HtrA2 in cells undergoing apoptosis. This protein is an uncharacterized member of the THAP family of proteins. THAP5 has a unique pattern of expression and is found predominantly in the human heart, although a very low expression is also seen in the human brain and muscle. THAP5 protein is localized in the nucleus and, when ectopically expressed, induces cell cycle arrest. During apoptosis, THAP5 protein is degraded, and this process can be blocked using a specific Omi/HtrA2 inhibitor, leading to reduced cell death. In patients with coronary artery disease, THAP5 protein levels substantially decrease in the myocardial infarction area, suggesting a potential role of this protein in human heart disease. This work identifies human THAP5 as a cardiac-specific nuclear protein that controls cell cycle progression. Furthermore, during apoptosis, THAP5 is cleaved and removed by the proapoptotic Omi/HtrA2 protease. Taken together, we provide evidence to support that THAP5 and its regulation by Omi/HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes.

scholarly journals Caffeine Sensitizes U87-MG Human Glioblastoma Cells to Temozolomide through Mitotic Catastrophe by Impeding G2 Arrest

2018 ◽  
Vol 2018 ◽  
pp. 1-10
Author(s):  
Ning Li ◽  
Pingde Zhang ◽  
Karrie Mei Yee Kiang ◽  
Yin Stephen Cheng ◽  
Gilberto Ka Kit Leung
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Combined Treatment ◽  
Mitotic Cell ◽  
Mitotic Catastrophe ◽  
Mechanistic Study ◽  
Anticancer Activities ◽  
G2 Arrest ◽  
Multipolar Spindle ◽  
Cycle Arrest

Temozolomide (TMZ) is the first-line chemotherapeutic agent in the treatment of glioblastoma multiforme (GBM). Despite its cytotoxic effect, TMZ also induces cell cycle arrest that may lead to the development of chemoresistance and eventual tumor recurrence. Caffeine, a widely consumed neurostimulant, shows anticancer activities and is reported to work synergistically with cisplatin and camptothecin. The present study aimed to investigate the effects and the mechanisms of action of caffeine used in combination with TMZ in U87-MG GBM cells. As anticipated, TMZ caused DNA damage mediated by the ATM/p53/p21 signaling pathway and induced significant G2 delay. Concurrent treatment with caffeine repressed proliferation and lowered clonogenic capacity on MTT and colony formation assays, respectively. Mechanistic study showed that coadministration of caffeine and TMZ suppressed the phosphorylation of ATM and p53 and downregulated p21 expression, thus releasing DNA-damaged cells from G2 arrest into premature mitosis. Cell cycle analysis demonstrated that the proportion of cells arrested in G2 phase decreased when caffeine was administered together with TMZ; at the same time, the amount of cells with micronucleation and multipolar spindle poles increased, indicative of enhanced mitotic cell death. Pretreatment of cells with caffeine further enhanced mitotic catastrophe development in combined treatment and sensitized cells to apoptosis when followed by TMZ alone. In conclusion, our study demonstrated that caffeine enhanced the efficacy of TMZ through mitotic cell death by impeding ATM/p53/p21-mediated G2 arrest.

scholarly journals CDK12/13 Inhibition Induces Immunogenic Cell Death and Enhances Anti-PD-1 Anticancer Activity in Breast Cancer

2020 ◽  
Author(s):  
Yi Li ◽  
Hui Zhang ◽  
Qin Li ◽  
Pingjin Zou ◽  
Xingxiang Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Cell Death ◽  
T Cell ◽  
Combined Treatment ◽  
Specific Inhibitor ◽  
T Cell Response ◽  
Immunogenic Cell Death ◽  
Mouse Tumor ◽  
Syngeneic Mouse Model

Abstract Background: The T cell response against different tumors is improved by immunogenic cell death (ICD), indicating a role for ICD in augmenting antitumor immunity elicited by the anti-checkpoint antibody anti-programmed death 1 (anti-PD-1). Methods: The effect of SR-4835 on breast cancer was analyzed by cell proliferation and flow cytometry. Calreticulin translocation and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of SR-4835 treated cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of maturation of BMDCs and production of IL-6 in the supernatant were measured. The in vivo antitumor effect was analyzed by syngeneic mouse model followed by flow cytometry for TILs.Results: In the present study, we report a synergistic and durable immune-mediated antitumor response elicited by the combined treatment of SR-4835, a CDK12/13 specific inhibitor, with PD-1 blockade in a murine model of 4T1 breast cancer. The developed combination therapy elicited antitumor activity in immunocompetent mouse tumor models. Furthermore, the SR-4835-treated tumor cells exhibited characteristics of ICD, including the release of high mobility group box 1 (HMGB1) and ATP and the translocation of surface calreticulin (CRT). This activity led to a significant T-cell dependent regression of tumors. The enhanced infiltration of T cells and dendritic cell (DC) activation in the tumors of mice treated with both SR-4835 and anti-PD-1 indicate that this combination treatment promotes an improved immune response and suggests a potential mechanism involving anti-PD-1 and SR-4835 activity that enhances anti-PD-1 effects. Conclusion: The results of the present study demonstrate the potential of CDK12/13 inhibition combined with checkpoint inhibition in breast cancer treatment.

COMBINATION OF POTASSIUM PERCHLORATE AND PROPYLTHIOURACIL IN THE TREATMENT OF THYROTOXICOSIS

1968 ◽  
Vol 57 (4) ◽  
pp. 565-577 ◽  
Author(s):  
K. E. Røkke ◽  
J. H. Vogt
Keyword(s):  
Drug Therapy ◽  
Side Effects ◽  
Metabolic Rate ◽  
Total Cholesterol ◽  
Basal Metabolic Rate ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Control Measures ◽  
Potassium Perchlorate ◽  
Plasma Total Cholesterol

ABSTRACT A report is given on 95 thyrotoxic patients treated with a combination of 400 mg propylthiouracil and 400 mg of potassium perchlorate. Perchlorate was stopped when a marked remission of symptoms was obtained, on an average after less than 7 weeks. Euthyroidism was found on an average after 7.2 weeks. The basal metabolic rate, PBI, plasma total cholesterol and weight showed a fairly rapid normalization. Thirteen of the 95 patients were given radio-iodine therapy shortly before drug therapy was started. The remaining 82 cases were grouped together with the 23 cases previously reported. Of the total of 105 cases, 96 became euthyroid on combined therapy. For the frequency of side-effects, the thirteen cases mentioned above were included, giving a total of 118 cases. Eight cases showed an increase in goitre size and 15 cases had other side-effects, of which three were granulocytopenia due to propylthiouracil. The possibility of a higher frequency of mainly minor side-effects on combined therapy has to be balanced against the seemingly rapid and reliable therapeutic effect. Combined treatment, perhaps with even smaller doses than reported here, can be recommended in selected cases of thyrotoxicosis where a shortening of the thyrotoxic state seems of importance, or possibly where difficulties due to iodine exposure may be anticipated, provided adequate control measures are taken.

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