scholarly journals Antrodin C, an NADPH Dependent Metabolism, Encourages Crosstalk between Autophagy and Apoptosis in Lung Carcinoma Cells by Use of an AMPK Inhibition-Independent Blockade of the Akt/mTOR Pathway

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 993 ◽  
Author(s):  
Hairui Yang ◽  
Xu Bai ◽  
Henan Zhang ◽  
Jingsong Zhang ◽  
Yingying Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Signaling Pathway ◽  
Lung Carcinoma ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Clinical Pharmacokinetics ◽  
Ampk Signaling ◽  
P53 Signaling ◽  
Lung Carcinoma Cells

The current study aims to explore the possible anti-lung carcinoma activity of ADC as well as the underlying mechanisms by which ADC exerts its actions in NSCLC. Findings showed that ADC potently inhibited the viability of SPCA-1, induced apoptosis triggered by ROS, and arrested the cell cycle at the G2/M phase via a P53 signaling pathway. Interestingly, phenomena such as autophagosomes accumulation, conversion of the LC3-I to LC3-II, etc., indicated that autophagy could be activated by ADC. The blockage of autophagy-augmented ADC induced inhibition of cell proliferation, while autophagy activation restored cell death, indicating that autophagy had a protective effect against cell death which was induced by ADC treatment. Meanwhile, ADC treatment suppressed both the Akt/mTOR and AMPK signaling pathways. The joint action of both ADC and the autophagy inhibitor significantly increased the death of SPCA-1. An in vitro phase I metabolic stability assay showed that ADC was highly metabolized in SD rat liver microsomes and moderately metabolized in human liver microsomes, which will assist in predicting the outcomes of clinical pharmacokinetics and toxicity studies. These findings imply that blocking the Akt/mTOR signaling pathway, which was independent of AMPK inhibition, could activate ADC-induced protective autophagy in non-small-cell lung cancer cells.

scholarly journals Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors β and γ, DN203368

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 776
Author(s):  
Sin-Eun Kim ◽  
Seung-Bae Ji ◽  
Euihyeon Kim ◽  
Minseon Jeong ◽  
Jina Kim ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Resolution ◽  
Human Liver ◽  
High Resolution Mass Spectrometry ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Rat Liver Microsomes ◽  
High Resolution Mass ◽  
Resolution Mass

DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor β/γ (ERRβ/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis and holds potential as a novel therapeutic target in metabolic diseases such as diabetes mellitus, obesity, and cancer. ERRβ is also one of the orphan nuclear receptors critical for many biological processes, such as development. We investigated the in vitro metabolism of DN203368 by conventional and metabolomic approaches using high-resolution mass spectrometry. The compound (100 μM) was incubated with rat and human liver microsomes in the presence of NADPH. In the metabolomic approach, the m/z value and retention time information obtained from the sample and heat-inactivated control group were statistically evaluated using principal component analysis and orthogonal partial least-squares discriminant analysis. Significant features responsible for group separation were then identified using tandem mass spectra. Seven metabolites of DN203368 were identified in rat liver microsomes and the metabolic pathways include hydroxylation (M1-3), N-oxidation (M4), N-deisopropylation (M5), N,N-dealkylation (M6), and oxidation and dehydrogenation (M7). Only five metabolites (M2, M3, and M5-M7) were detected in human liver microsomes. In the conventional approach using extracted ion monitoring for values of mass increase or decrease by known metabolic reactions, only five metabolites (M1-M5) were found in rat liver microsomes, whereas three metabolites (M2, M3, and M5) were found in human liver microsomes. This study revealed that nontargeted metabolomics combined with high-resolution mass spectrometry and multivariate analysis could be a more efficient tool for drug metabolite identification than the conventional approach. These results might also be useful for understanding the pharmacokinetics and metabolism of DN203368 in animals and humans.

In vitro metabolism in Sprague–Dawley rat liver microsomes of forsythoside A in different compositions of Shuang–Huang–Lian

Fitoterapia ◽  
2011 ◽  
Vol 82 (8) ◽  
pp. 1222-1230 ◽  
Author(s):  
Wei Zhou ◽  
Liu-qing Di ◽  
Jin-jun Shan ◽  
Xiao-lin Bi ◽  
Le-tian Chen ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
In Vitro Metabolism ◽  
Rat Liver Microsomes ◽  
Sprague Dawley ◽  
Sprague Dawley Rat

scholarly journals In Vitro Characterization of Borneol Metabolites by GC--MS Upon Incubation with Rat Liver Microsomes

2008 ◽  
Vol 46 (5) ◽  
pp. 419-423 ◽  
Author(s):  
R. Zhang ◽  
C.-h. Liu ◽  
T.-l. Huang ◽  
N.-s. Wang ◽  
S.-q. Mi
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
In Vitro Characterization

In Vitro Metabolism of E2, G2: Novel Bile Acid-Coupling Camptothecin Analogues, in Rat Liver Microsomes

2021 ◽  
Vol 16 ◽  
Author(s):  
Xiangli Zhang ◽  
Qin Shen ◽  
Yi Wang ◽  
Leilei Zhou ◽  
Qi Weng ◽  
...  
Keyword(s):  
Bile Acid ◽  
Phase I ◽  
Rat Liver ◽  
Deoxycholic Acid ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Rat Liver Microsomes ◽  
Camptothecin Analogues

Background: E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues by introducing deoxycholic acid in 20-position of CPT(camptothecin) with greater anticancer activity and lower systematic toxicity in vivo. Objective: We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). Methods: Phase Ⅰ and Phase Ⅱ metabolism of E2 and G2 in rat liver microsomes were performed respectively, and the mixed incubation of phase I and phase Ⅱ metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. Results: The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some difference. The intrinsic clearance of G2 was 174.7mL/min. mg protein, more than three times of that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations and hydrolysis) and their further glucuronidation products. Conclusion: These findings suggested that E2 and G2 have similar biotransformation pathways except some difference in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).

scholarly journals LSD1 modulates the non-canonical integrin β3 signaling pathway in non-small cell lung carcinoma cells

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
So-Young Lim ◽  
Iris Macheleidt ◽  
Priya Dalvi ◽  
Stephan C. Schäfer ◽  
Martin Kerick ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Carcinoma Cells ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Integrin Β3 ◽  
Lung Carcinoma Cells

scholarly journals Effect of Micelle-Incorporated Cisplatin With Sizes Ranging From 8 to 40 nm for the Therapy of Lewis Lung Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhicheng Wang ◽  
Yumin Li ◽  
Tong Zhang ◽  
Hongxia Li ◽  
Zhao Yang ◽  
...  
Keyword(s):  
Block Copolymers ◽  
Lung Carcinoma ◽  
Lewis Lung Carcinoma ◽  
Drug Loading ◽  
Complexation Reaction ◽  
Lewis Lung ◽  
Antitumor Effects ◽  
Lung Carcinoma Cells

Insufficient transport of therapeutic cargo into tumor bed is a bottleneck in cancer nanomedicine. Block copolymers are promising carriers with smaller particle size by ratio modification. Here, we constructed cisplatin nanoparticles with sizes ranging from 8 to 40 nm to study the permeability and therapy of Lewis lung carcinoma. We synthesized methoxypoly(ethylene glycol)2000-block poly(L-glutamic acid sodium salt)1979 loading cisplatin through complexation reaction. The cisplatin nanomedicine has high drug loading and encapsulation efficiency. In vitro data demonstrated that cisplatin nanoparticles had equivalent growth-inhibiting effects on Lewis lung carcinoma cells compared to free cisplatin. In vivo evidences showed cisplatin nanoparticles had superior antitumor effects on the Lewis lung carcinoma mouse model with no obvious side effects. All results indicated that optimizing the ratio of block copolymers to obtain smaller sized nanomedicine could act as a promising strategy for overcoming the inadequate accumulation in poorly vascularized tumors.

scholarly journals Gold Nanoparticles Radio-sensitize and Reduce Cell Survival in Lewis Lung Carcinoma

2020 ◽  
Author(s):  
Arvind Pandey ◽  
Veronica Vighetto ◽  
Nicola Di Marzio ◽  
Matteo Hirsch ◽  
Nicola Ferrante ◽  
...  
Keyword(s):  
Dna Damage ◽  
Particle Size ◽  
Gold Nanoparticles ◽  
Cell Survival ◽  
Lung Carcinoma ◽  
Lewis Lung Carcinoma ◽  
Lewis Lung ◽  
Lung Carcinoma Cells ◽  
Reduce Cell Survival

It has been suggested that particle size plays an important role in determining the genotoxicity of gold nanoparticles (GNPs). The purpose of this study was to compare the potential radio-sensitization effects of two different sized GNPs (3.9 and 37.4 nm) fabricated and examined in vitro in Lewis Lung carcinoma (LLC) as a model of non-small cell lung cancer through use of comet and clonogenic assays. After the treatment of 2Gy X-ray irradiation, both particle sizes demonstrated increased DNA damage when compared to treatment with particles only and radiation alone. This radio-sensitization was further translated into a reduction in cell survival demonstrated by clonogenicity. This work indicates that GNPs of both sizes induce DNA damage in LLC cells at the tested concentrations, whereas the 37.4 nm particle size treatment group demonstrated greater significance in vitro. The presented data aids in the evaluation of the radiobiological response of Lewis Lung carcinoma cells treated with gold nanoparticles.

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