scholarly journals Are There Thresholds in Glioblastoma Cell Death Responses Triggered by Temozolomide?

2019 ◽  
Vol 20 (7) ◽  
pp. 1562 ◽  
Author(s):  
Yang He ◽  
Bernd Kaina

Temozolomide (TMZ) is an alkylating agent used in the treatment of high-grade malignant glioma, notably glioblastoma multiforme, the most aggressive form of brain cancer. The drug induces a dozen DNA methylation adducts, including O6-methylguanine (O6MeG), which is the most toxic primary DNA lesion as it causes the formation of DNA double-strand breaks (DSBs) that trigger apoptosis. In p53 wild-type cells, TMZ activates p-p53ser15 and p-p53ser46, which have opposing dual functions regulating survival and death, respectively. Since the use of TMZ in a therapeutic setting is limited because of its side effects, the question arises as to the existence of threshold doses that activate the death pathway and start apoptosis. To determine whether there is a threshold for the TMZ-induced DNA damage response and exploring the factors regulating the switch between p53 dependent survival and death, the glioblastoma lines LN-229 (deficient in MGMT) and LN-229MGMT (stably transfected with MGMT) were exposed to different doses of TMZ. p53 protein expression and phosphorylation levels of p-p53ser15 and p-p53ser46 were determined by Western blotting. Also, apoptosis, senescence and autophagy levels were checked after different doses of TMZ. The results show that pro-survival p-p53ser15 and pro-death p-p53ser46 were induced by O6MeG in a specific dose- and time-dependent manner. p-p53ser15 was an early response while p-p53ser46 was activated at later times following treatment. Unexpectedly, the dose-response curves for total p53, p-p53ser15 and p-p53ser46 were linear, without an obvious threshold. O6MeG induces apoptosis late after treatment as a linear function of TMZ dose. This was observed for both p53 proficient LN-229 and p53 lacking LN-308 cells. A linear dose-response after TMZ was also observed for senescence and autophagy as well as γH2AX, an indicator of DSBs that are considered to be the downstream trigger of apoptosis, senescence and autophagy. LN-229MGMT cells were highly resistant to all measured endpoints because of repair of the critical primary lesion. Although LN-308 were less responsive than LN-229 to TMZ, they displayed the same TMZ-induced DSB level. The observed linear dose-responses are not compatible with the view that low DNA damage level evokes survival while high damage level activates death functions. The data bear important therapeutic implications as they indicate that even low doses of TMZ may elicit a cytotoxic response. However, since O6MeG triggers apoptosis, senescence and autophagy in the same dose range, it is likely that the accumulation of senescent cells in the population counteracts the killing effect of the anticancer drug.

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.


Agronomy ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1735
Author(s):  
Candelario Palma-Bautista ◽  
Pablo Belluccini ◽  
Valentin Gentiletti ◽  
José G. Vázquez-García ◽  
Hugo E. Cruz-Hipolito ◽  
...  

Carduus acanthoides L. is an invasive species native to Europe and distributed in other parts of the world, including North and South America. In Cordoba, Argentina, control failures of this species have been reported in Roundup Ready (RR) soybean crops where glyphosate and 2,4-D have frequently been applied, although there are no confirmed reports worldwide of resistance to glyphosate and 2,4-D in this species. Dose–response tests showed multiple-resistance to both active principles. The resistant population (R) had LD50 values of 1854.27 and 1577.18 g ae ha−1 (grams of acid equivalent per hectare), while the susceptible (S) population had LD50 values of 195.56 and 111.78 g ae ha−1 for glyphosate and 2,4-D, respectively. Low accumulations of shikimic acid (glyphosate) and ethylene (2,4-D) at different doses in the R population compared to the S population support the results observed in the dose–response curves. No significant differences in leaf retention were observed for glyphosate and 2,4-D in the R and S populations. However, the use of adjuvants increased the retention capacity of herbicides in both populations. Ten alternative herbicides with seven different action mechanisms (MOAs) were evaluated and the most effective active principles were dicamba, bromoxynil, atrazine, tembotrione, flazasulfuron, glufosinate, and paraquat. These findings are the first evidence of glyphosate and 2,4 D resistance in C. acanthoides.


2020 ◽  
Vol 47 (1) ◽  
pp. 71-92
Author(s):  
Zhenjun Li ◽  
Xuesong Mou ◽  
Yuxin Fan ◽  
Qingsong Zhang ◽  
Guangliang Yang ◽  
...  

AbstractEstablishing a common standardised growth curve (SGC) can substantially reduce the instrumental time for equivalent-dose (De) measurements in optically stimulated luminescence (OSL) dating. Several studies have indicated that different samples have different dose–response curves (DRCs) and therefore that it is difficult to construct a common SGC, although an SGC has been proposed in some cases. In this study, our aims were to construct a regional SGC based on small aliquots of sedimentary quartz from more than 100 samples from different sedimentary environments in the Jilantai Basin in North China and to investigate the applicability of different methods of establishing an SGC for the area. The precision of the De values of aliquots which were obtained using the SGC was compared with those obtained using the single-aliquot regenerative (SAR) protocol. Our results indicate the following: (1) for establishing an SGC using the regenerative normalisation (Re-SGC) method, selecting a suitable re-normalisation dose that is close to double the characteristic saturation dose, 2D0, can reduce the inter-aliquot/inter-sample variation in the form of DRCs within a larger dose range. (2) A common regional SGC can be established for the Jilantai area using the Re-SGC and least-squares normalisation (LS-SGC) methods, which provides reliable dating results within the 200 Gy De range.


2000 ◽  
Vol 93 (1) ◽  
pp. 219-230 ◽  
Author(s):  
Margarita M. Puig ◽  
William Warner ◽  
Olga Pol

Background Morphine and clonidine show synergy or antagonism inhibiting gastrointestinal transit depending on their proportion and level of effect. Their interaction during morphine tolerance and intestinal inflammation were assessed. Methods Gastrointestinal transit in mice was evaluated with charcoal and antitransit effects expressed as percent mean values +/- SEM. Tolerance was induced with a morphine pellet (75 mg) implanted for 72 h, and inflammation with intragastric croton oil. Dose-response curves for morphine and clonidine alone and combined at a 1:1 potency ratio were obtained, and doses producing a 50% and 60% inhibition were calculated (ED50, ED60). Interaction was established by isobolograms, interaction indexes, and analysis of variance. Results In naive and tolerant mice, the combination induced linear dose-response curves up to the ED60 and then reached a plateau. In naive mice, ED50 values were as follows: morphine 1.52 +/- 0.15 mg/kg, clonidine 0.09 +/- 0.008 mg/kg, and combined 0.506 +/- 0.084 mg/kg (0.478 +/- 0.08 mg/kg morphine plus 0.028 +/- 0.004 mg/kg clonidine). During tolerance, ED50 values were as follows: morphine 9.73 +/- 0.8 mg/kg, clonidine 0.09 +/- 0.007 mg/kg, combination 0.131 +/- 0.09 mg/kg (morphine 0. 13 +/- 0.09 mg/kg plus clonidine 0.0013 +/- 0.0005 mg/kg). In both groups, the interaction was synergistic up to the ED60 and antagonistic thereafter; synergy was enhanced during tolerance. During inflammation, ED50 values were as follows: morphine 0.17 +/- 0.04 mg/kg, clonidine 0.015 +/- 0.006 mg/kg, combined 0.62 +/- 0.04 mg/kg (morphine 0.568 +/- 0.04 mg/kg plus clonidine 0.052 +/- 0.004 mg/kg); thus, potencies of morphine and clonidine increased 9.3 and 7.1 times, while the combination remained unaltered. Moreover, inflammation transformed synergy into antagonism. Conclusions The interaction between morphine and clonidine was significantly altered during tolerance and inflammation. During tolerance, synergy was present up to 60% effect and then became antagonistic. Inflammation converted synergy to antagonism. A common pathway in signal transduction could partially explain the results.


1984 ◽  
Vol 66 (6) ◽  
pp. 665-673 ◽  
Author(s):  
K. F. Chung ◽  
P. D. Snashall

1. The bronchial response of 11 normal and ten stable asthmatic subjects to increasing concentrations of methacholine aerosol was assessed by serial measurements of specific airways conductance (scaw) in a body plethysmograph. 2. Cumulative log dose-response curves were constructed. The threshold provocative dose of methacholine needed to cause a 35% fall in starting sCaw (pD35) and the steepest slope of the response were measured from each curve. 3. On separate days subjects were premedicated with 0.9% NaCl solution (control) in duplicate, chlorpheniramine, salbutamol and atropine, the last-named at two different doses, one twice the other. 4. Asthmatic subjects had a lower mean PD35 and a lower mean slope than normal subjects. 5. Pretreatment with salbutamol resulted in a greater increase in sGaw than after atropine but caused a smaller increase in PD35 in both groups. There was a dose-dependent increase in PD3s after the two doses of atropine, but no significant difference in bronchodilatation between doses. Mean steepest slope approximately doubled in these three sets of challenges. 6. Chlorpheniramine caused a small degree of bronchodilatation and there was a non-significant increase in mean PD3s and in mean steepest slope in both normal and asthmatic groups. 7. There was a positive linear correlation between starting sGaw and steepest slope in each group of premedicated challenges, such that when


2021 ◽  
Vol 50 (9) ◽  
pp. 2687-2700
Author(s):  
Amber Hanif Palla ◽  
Najeeb Ur Rehman ◽  
Hasan Salman Siddiqi ◽  
Anwar-Ul-Hassan Gilani ◽  
Bina Shaheen Siddiqui ◽  
...  

Linum usitatissimum (Flaxseed) is known to be traditionally used for managing hypertension. In this study, we aim to provide a mechanistic basis for the medicinal use of Flaxseed in hypertension. The high-performance liquid chromatography (HPLC) analysis that we carried out during our study showed the presence of polar compounds (quercetin, nicotinic acid, and nicotinamide) in Flaxseed’s crude extract (Fs.Cr; aqueous methanolic). In anesthetized rats, Fs.Cr reduced arterial blood pressure (BP) dose-dependently (10-100 mg/kg). When tested for its mechanism of action ex vivo, Fs.Cr inhibited both the force and rate of spontaneous contractions in the dose range of 1-10 mg/mL in isolated guinea-pig atria, similar to how verapamil, a standard Ca+2 channel blocker does it. Further, Fs.Cr showed vasodilator effect against the contractions induced by phenylephrine (PE, 1 μM) in rat aortic ring preparations (concentration range: 1-10 mg/mL), whereas no effect was observed against the contractions induced by low K+ (25 mM) as well as high K+ (80 mM). This selective inhibitory effect of Fs.Cr against PE was tested for endothelium-dependent nitric oxide (NO) and/or cholinergic component involvement. The vasodilator effect of Fs.Cr against PE was retested in the absence and presence of atropine in endothelium (E)-intact and E-denuded aorta, but no significant shift was observed in the inhibitory effect of Fs.Cr. Further, Fs.Cr shifted the PE-induced concentration-response curves (CRCs) to the right in a dose-dependent manner (1 and 3 mg/mL). This effect was similar to that of prazosin. All these findings indicate that Flaxseed may mediate its antihypertensive activity by the alpha-1 receptor antagonist and Ca+2 channel blocking-like activity, which may account for its efficacy in hypertension.


2005 ◽  
Vol 29 (3) ◽  
pp. 104-107 ◽  
Author(s):  
David Taylor

Aims and MethodThe aim of this literature analysis was to establish the range of doses of haloperidol decanoate effective in preventing relapse in schizophrenia. Studies reporting relapse rates in patients treated for longer than 6 months were included. Relapse rate was then plotted against dose or log dose to allow drawing of dose–response curves.ResultsFifteen publications reporting 13 individual studies were identified. of these, 6 studies met inclusion criteria and were analysed. Dose–response curves indicated limited effect at 25 mg/4 weeks but near maximal effect at doses of 50 mg/4 weeks. There was no clear evidence that increasing the dose above 100 mg/4 weeks provided additional benefit in preventing relapse.Clinical ImplicationsThe recommended dose range for haloperidol decanoate (50–300 mg/ 4 weeks) does not reflect the findings of this study. Optimally effective doses appear to be around 50–100 mg/4 weeks. The use of doses above 100 mg/4 weeks is difficult to support given data available.


Mutagenesis ◽  
2008 ◽  
Vol 23 (5) ◽  
pp. 399-405 ◽  
Author(s):  
G. J. S. Jenkins ◽  
J. Cronin ◽  
A. Alhamdani ◽  
N. Rawat ◽  
F. D'Souza ◽  
...  

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