scholarly journals Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor

2020 ◽  
Vol 8 ◽  
Author(s):  
Jing-Quan Wang ◽  
Qiu-Xu Teng ◽  
Zi-Ning Lei ◽  
Ning Ji ◽  
Qingbin Cui ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Kinase Inhibitor ◽  
Efflux Pump ◽  
Simulation Analysis ◽  
Chemotherapeutic Agents ◽  
Dynamics Simulation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Raf Kinase

Overexpression of ABCG2 remains a major impediment to successful cancer treatment, because ABCG2 functions as an efflux pump of chemotherapeutic agents and causes clinical multidrug resistance (MDR). Therefore, it is important to uncover effective modulators to circumvent ABCG2-mediated MDR in cancers. In this study, we reported that AZ-628, a RAF kinase inhibitor, effectively antagonizes ABCG2-mediated MDR in vitro. Our results showed that AZ-628 completely reversed ABCG2-mediated MDR at a non-toxic concentration (3 μM) without affecting ABCB1-, ABCC1-, or ABCC10 mediated MDR. Further studies revealed that the reversal mechanism was by attenuating ABCG2-mediated efflux and increasing intracellular accumulation of ABCG2 substrate drugs. Moreover, AZ-628 stimulated ABCG2-associated ATPase activity in a concentration-dependent manner. Docking and molecular dynamics simulation analysis showed that AZ-628 binds to the same site as ABCG2 substrate drugs with higher score. Taken together, our studies indicate that AZ-628 could be used in combination chemotherapy against ABCG2-mediated MDR in cancers.

scholarly journals Reversal of Ovarian Cancer Cell Lines Multidrug Resistance Phenotype by the Association of Apiole with Chemotherapies

2020 ◽  
Vol 13 (10) ◽  
pp. 327
Author(s):  
Carolina Afonso de Lima ◽  
Ian Lucas de Souza Bueno ◽  
Stanley Nunes Siqueira Vasconcelos ◽  
Juliana Mozer Sciani ◽  
Ana Lúcia Tasca Gois Ruiz ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Calcium Channel ◽  
Efflux Pump ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Channel Blockers ◽  
Dependent Manner ◽  
Tumor Resistance ◽  
Concentration Dependent Manner ◽  
Chemotherapy Drugs

Multidrug resistance (MDR) is the main obstacle in anticancer therapy. The use of drug combinations to circumvent tumor resistance is a well-established principle in the clinic. Among the therapeutic targets, glycoprotein-P (P-gp), an energy-dependent transmembrane efflux pump responsible for modulating MDR, is highlighted. Many pharmacological studies report the ability of calcium channel blockers to reverse tumor resistance to chemotherapy drugs. Isolated for the first time from parsley, the phenylpropanoid apiole is described as a potent calcium channel inhibitor. Taking this into account, herein, the ability of apiole to potentiate the action of well-established chemotherapeutics in the clinic, as well as the compound’s relationship with the reversal of the resistance phenomenon by blocking P-gp, is reported. The association of apiole with both chemotherapeutic drugs doxorubicin and vincristine resulted in synergistic effect, in a concentration-dependent manner, as evaluated by the concentration reduction index. Molecular docking analysis demonstrated the affinity between apiole and the active site of P-gp, corroborating the inhibitory effect. Moreover, apiole demonstrated druglikeness, according to ADME analysis. In conclusion, apiole possibly blocks the active P-gp site, with strong binding energy, which, in turn, inhibits doxorubicin and vincristine efflux, increasing the antiproliferative response of these chemotherapeutic agents.

scholarly journals Antioxidant, Anti-Inflammatory, and Multidrug Resistance Modulation Activity of Silychristin Derivatives

Antioxidants ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 303 ◽  
Author(s):  
Jitka Viktorová ◽  
Simona Dobiasová ◽  
Kateřina Řehořová ◽  
David Biedermann ◽  
Kristýna Káňová ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
No Production ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Modulation

Silychristin A is the second most abundant compound of silymarin. Silymarin complex was previously described as an antioxidant with multidrug resistance modulation activity. Here, the results of a classical biochemical antioxidant assay (ORAC) were compared with a cellular assay evaluating the antioxidant capacity of pure silychristin A and its derivatives (anhydrosilychristin, isosilychristin and 2,3-dehydrosilychristin A). All the tested compounds acted as antioxidants within the cells, but 2,3-dehydro- and anhydro derivatives were almost twice as potent as the other tested compounds. Similar results were obtained in LPS-stimulated macrophages, where 2,3-dehydro- and anhydrosilychristin inhibited NO production nearly twice as efficiently as silychristin A. The inhibition of P-glycoprotein (P-gp) was determined in vitro, and the respective sensitization of doxorubicin-resistant ovarian carcinoma overproducing P-gp was detected. Despite the fact that the inhibition of P-gp was demonstrated in a concentration-dependent manner for each tested compound, the sensitization of the resistant cell line was observed predominantly for silychristin A and 2,3-dehydrosilychristin A. However, anhydrosilychristin and isosilychristin affected the expression of both the P-gp (ABCB1) and ABCG2 genes. This is the first report showing that silychristin A and its 2,3-dehydro-derivative modulate multidrug resistance by the direct inhibition of P-gp, in contrast to anhydrosilychristin and isosilychristin modulating multidrug resistance by downregulating the expression of the dominant transmembrane efflux pumps.

Lysophosphatidic acid rapidly induces protein kinase D activation through a pertussis toxin-sensitive pathway

2000 ◽  
Vol 278 (1) ◽  
pp. C33-C39 ◽  
Author(s):  
Lina Paolucci ◽  
James Sinnett-Smith ◽  
Enrique Rozengurt
Keyword(s):  
Protein Kinase ◽  
Pertussis Toxin ◽  
Lysophosphatidic Acid ◽  
Kinase Inhibitor ◽  
Structural Features ◽  
Protein Kinase D ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Swiss 3T3

Protein kinase D (PKD) is a serine-threonine protein kinase with distinct structural features and enzymological properties. Herein we demonstrate that lysophosphatidic acid (LPA) induces rapid PKD activation in mouse Swiss 3T3 and Rat-1 cells. LPA induced PKD activation in a concentration-dependent fashion with maximal stimulation (7.6-fold) achieved at 5 μM. Treatment of Swiss 3T3 cells with the protein kinase C (PKC) inhibitors GF-I, Ro-31–8220, and Gö-7874 completely abrogated PKD activation induced by LPA at concentrations that did not inhibit PKD activity when added directly to the in vitro kinase assays. PKD activation induced by LPA was attenuated markedly and selectively by prior exposure of either Swiss 3T3 or Rat-1 cells to pertussis toxin (PTx) in a concentration-dependent manner. In contrast, treatment with the protein tyrosine kinase inhibitor genistein, the MEK inhibitor PD-098059, or the phosphoinositide 3-kinase inhibitor wortmannin did not affect PKD activation in response to LPA. These results provide the first example of PTx-sensitive and PKC-dependent PKD activation and identify a novel Gi-dependent event in the action of LPA.

scholarly journals Taxifolin Resensitizes Multidrug Resistance Cancer Cells via Uncompetitive Inhibition of P-Glycoprotein Function

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3055 ◽  
Author(s):  
Hsiu-Ju Chen ◽  
Yun-Lung Chung ◽  
Chia-Ying Li ◽  
Ying-Tzu Chang ◽  
Charles Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Uncompetitive Inhibition ◽  
P Glycoprotein

P-glycoprotein (P-gp) effluxes lots of chemotherapeutic agents and leads to multidrug resistance (MDR) in cancer treatments. The development of P-gp inhibitors from natural products provide a potential strategy for the beneficial clinical outcomes. This study aimed to evaluate the effects of the natural flavonoid taxifolin, luteolin, (−)-gallocatechin, and (−)-catechin on human P-gp activity. The kinetic interactions and underlying mechanisms of taxifolin-mediated transporter inhibition were further investigated. The transporter inhibition ability was evaluated in human P-gp stable expression cells (ABCB1/Flp-InTM-293) by calcein-AM uptake assays. The kinetics study for P-gp inhibition was evaluated by doxorubicin and rhodamine123 efflux assays. The MDR reversal ability of taxifolin were performed by SRB assays to detect the cell viability in sensitive cancer cell line (HeLaS3), and resistant cancer cell line (KB-vin). Cell cycle analysis and ABCB1 real-time RT-PCR were used for mechanical exploration. The results demonstrated that taxifolin decreased ABCB1 expression in a concentration-dependent manner. The function of P-gp was inhibited by taxifolin through uncompetitive inhibition of rhodamine 123 and doxorubicin efflux. The combination of taxifolin significantly resensitized MDR cancer cells to chemotherapeutic agents. These results suggested that taxifolin may be considered as a potential P-gp modulator for synergistic treatment of MDR cancers.

scholarly journals Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 195 ◽  
Author(s):  
Chung-Pu Wu ◽  
Sung-Han Hsiao ◽  
Yang-Hui Huang ◽  
Lang-Cheng Hung ◽  
Yi-Jou Yu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Kinase Inhibitor ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Dependent Manner ◽  
Chemotherapeutic Drugs ◽  
Concentration Dependent Manner ◽  
Novel Therapeutic Strategies

The development of multidrug resistance (MDR) in cancer patients driven by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells presents one of the most daunting therapeutic complications for clinical scientists to resolve. Despite many novel therapeutic strategies that have been tested over the years, there is still no approved treatment for multidrug-resistant cancers to date. We have recently adopted a drug repurposing approach to identify therapeutic agents that are clinically active and at the same time, capable of reversing multidrug resistance mediated by ABCB1 and ABCG2. In the present study, we investigated the effect of sitravatinib, a novel multitargeted receptor tyrosine kinase inhibitor, on human ABCB1 and ABCG2 in multidrug-resistant cancer cell lines. We discovered that at submicromolar concentrations, sitravatinib re-sensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. We found that sitravatinib blocks the drug efflux function of ABCB1 and ABCG2 in a concentration-dependent manner but does not significantly alter the protein expression of ABCB1 or ABCG2 in multidrug-resistant cancer cells. In conclusion, we reveal a potential drug repositioning treatment option for multidrug-resistant cancers by targeting ABCB1 and ABCG2 with sitravatinib and should be further investigated in future clinical trials.

143 Galunisertib Exerts Targeted Anti-Fibrotic Effects in In Vitro Models of Burn Wound Healing

2021 ◽  
Vol 42 (Supplement_1) ◽  
pp. S95-S95
Author(s):  
Joshua M Peterson ◽  
Anesh Prasai ◽  
Jayson W Jay ◽  
Steven E Wolf ◽  
Amina El Ayadi
Keyword(s):  
Wound Healing ◽  
Protein Expression ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Burn Injury ◽  
Dependent Manner ◽  
Burn Wound ◽  
Concentration Dependent Manner ◽  
Burn Scar

Abstract Introduction Inhibition of TGF-β has shown promising in vitro and in vivo results for reduction of hypertrophic scarring after burn injury. However, TGF-β regulates diverse cellular pathways apart from fibrosis, including physiologic wound healing, cell cycle control, and homeostasis. Galunisertib, a novel small molecular tyrosine kinase inhibitor of TGF-beta receptor type 1, specifically targets downstream pro-fibrotic pathways of TGF-β signaling, has an excellent adverse effect profile, and minimal off-target effects. We hypothesized that galunisertib diminishes fibrotic phenotypes in a targeted fashion, making it a promising candidate drug for prevention of hypertrophic burn scar and contracture. Methods Commercially available fibroblasts were treated with TGF-β at concentrations typical of burn wounds to induce fibrotic phenotype fibroblasts (FPF). FPF cells were treated with galunisertib for 0, 1, 2, 3, and 7 days at concentrations ranging from 0.01 μM to 100 μM. FPF viability and proliferation were assessed with MTT assay. Modulation of FPF cell fibrotic gene and was analyzed using quantitative real-time PCR (qRT-PCR) of COL1A1, COL3A1, FN1, αSMA, CTGF, DCN, MMP1, and MMP13. Analysis of phenotype modulation was performed by western blotting of P-Smad2/3, collagen-1, fibronectin, and αSMA. Statistical analysis performed with students t-test and ANOVA. Results TGF-β treated FPF cells had significantly increased proliferation relative to commercially available fibroblasts, which was attenuated by treatment with 2.5–10 μM galunisertib at 2 or 3 days after treatment in a concentration dependent manner (p < 0.05) while also not causing a relative decrease in proliferation. Expression of FPF downstream pro-fibrotic genes underwent significant fold changes (FN1, αSMA, CTGF: p < 0.05). Protein expression showed decrease in both SMAD2/3 phosphorylation and fibrotic protein expression. Scratch assay analysis is ongoing. Conclusions Galunisertib exerts targeted dose-dependent inhibition of fibrotic gene expression and phenotypes in vitro without hindering cellular proliferation.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

Improved Method for Obtaining of Arctigenin from Arctium Lappa L. and its Antiproliferative Effect on Human Hepatocarcinoma HepG2 Cells

2020 ◽  
Vol 16 (3) ◽  
pp. 358-362
Author(s):  
Renan S. Teixeira ◽  
Paulo H.D. Carvalho ◽  
Jair A.K. Aguiar ◽  
Valquíria P. Medeiros ◽  
Ademar A. Da Silva Filho ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Crude Extract ◽  
Hepg2 Cells ◽  
Liver Carcinoma ◽  
Adhesion Assay ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Arctium Lappa ◽  
Nih 3T3

Background: Arctigenin is a lignan found in Arctium lappa L. (Asteraceae) that displays anti-inflammatory activities. Previous studies showed that the crude extract of A. Lappa has antitumor activity in human liver carcinoma, lung and stomach cancer cells. The aim of this study was to obtain arctigenin from A. lappa L., as well as to evaluate its antiproliferative effects in cells of liver carcinoma (HepG2) and fibroblasts (NIH/3T3). Methods: Arctigenin was obtained from the hydrolysis of arctiin, which was isolated from the crude extract of A. lappa. The effects of arctigenin and arctiin on HepG2 cell viability and cell adhesion were analyzed by MTT method. Adhesion assay was also carried out to evaluate the antitumor activity. Results: Our results showed that the analytical process to obtain arctigenin was fast and easy. In vitro experiments showed that arctigenin (107-269 μM) decreased HepG2 cells viability and did not cause cytotoxicity on NIH/3T3 cells. Arctigenin (27-269 μM) demonstrated anti-adhesion in HepG2 cells in a concentration-dependent manner, when compared with control. Conclusion: These results suggest a promising pharmacological activity for arctigenin as an antiproliferative compound.

scholarly journals Human Neuronal Cell Lines as An In Vitro Toxicological Tool for the Evaluation of Novel Psychoactive Substances

2021 ◽  
Vol 22 (13) ◽  
pp. 6785
Author(s):  
Valeria Sogos ◽  
Paola Caria ◽  
Clara Porcedda ◽  
Rafaela Mostallino ◽  
Franca Piras ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell ◽  
In Vitro Study ◽  
Dependent Manner ◽  
Novel Psychoactive Substances ◽  
Psychoactive Substances ◽  
Concentration Dependent Manner ◽  
Mechanisms Of Toxicity ◽  
Neuronal Cell Lines

Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing a considerable challenge for prevention and treatment. The present in vitro study investigated the possible mechanisms of toxicity of two emerging NPS (i) 4′-methyl-alpha-pyrrolidinoexanophenone (3,4-MDPHP), a synthetic cathinone, and (ii) 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA), a phenethylamine. In addition, to apply our model to the class of synthetic opioids, we evaluated the toxicity of fentanyl, as a reference compound for this group of frequently abused substances. To this aim, the in vitro toxic effects of these three compounds were evaluated in dopaminergic-differentiated SH-SY5Y cells. Following 24 h of exposure, all compounds induced a loss of viability, and oxidative stress in a concentration-dependent manner. 2-Cl-4,5-MDMA activates apoptotic processes, while 3,4-MDPHP elicits cell death by necrosis. Fentanyl triggers cell death through both mechanisms. Increased expression levels of pro-apoptotic Bax and caspase 3 activity were observed following 2-Cl-4,5-MDMA and fentanyl, but not 3,4-MDPHP exposure, confirming the different modes of cell death.

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