scholarly journals Semi-Synthesis, Cytotoxic Evaluation, and Structure—Activity Relationships of Brefeldin A Derivatives with Antileukemia Activity

Marine Drugs ◽  
2021 ◽  
Vol 20 (1) ◽  
pp. 26
Author(s):  
Xu-Xiu Lu ◽  
Yao-Yao Jiang ◽  
Yan-Wei Wu ◽  
Guang-Ying Chen ◽  
Chang-Lun Shao ◽  
...  
Keyword(s):  
Brefeldin A ◽  
K562 Cells ◽  
Inhibitory Effect ◽  
Marine Fungus ◽  
Myelogenous Leukemia ◽  
Cytotoxic Activities ◽  
Dependent Manner ◽  
Structure Activity Relationships ◽  
Structure Activity

Brefeldin A (1), a potent cytotoxic natural macrolactone, was produced by the marine fungus Penicillium sp. (HS-N-29) from the medicinal mangrove Acanthus ilicifolius. Series of its ester derivatives 2−16 were designed and semi-synthesized, and their structures were characterized by spectroscopic methods. Their cytotoxic activities were evaluated against human chronic myelogenous leukemia K562 cell line in vitro, and the preliminary structure–activity relationships revealed that the hydroxy group played an important role. Moreover, the monoester derivatives exhibited stronger cytotoxic activity than the diester derivatives. Among them, brefeldin A 7-O-2-chloro-4,5-difluorobenzoate (7) exhibited the strongest inhibitory effect on the proliferation of K562 cells with an IC50 value of 0.84 µM. Further evaluations indicated that 7 induced cell cycle arrest, stimulated cell apoptosis, inhibited phosphorylation of BCR-ABL, and thereby inactivated its downstream AKT signaling pathway. The expression of downstream signaling molecules in the AKT pathway, including mTOR and p70S6K, was also attenuated after 7-treatment in a dose-dependent manner. Furthermore, molecular modeling of 7 docked into 1 binding site of an ARF1–GDP-GEF complex represented well-tolerance. Taken together, 7 had the potential to be served as an effective antileukemia agent or lead compound for further exploration.

scholarly journals New Values of Teucrium species: in Vitro Study of Cytotoxic Activities of Secondary Metabolites

2015 ◽  
Vol 43 (1) ◽  
pp. 41-46 ◽  
Author(s):  
Milan S. STANKOVIĆ ◽  
Tatjana Lj. MITROVIĆ ◽  
Ivana Z. MATIĆ ◽  
Marina D. TOPUZOVIĆ ◽  
Slaviša M. STAMENKOVIĆ
Keyword(s):  
Cell Survival ◽  
Cytotoxic Effect ◽  
Mononuclear Cells ◽  
In Vitro Study ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
Breast Adenocarcinoma ◽  
Cytotoxic Activities ◽  
Peripheral Blood Mononuclear

The cytotoxicity of seven Teucrium species, a long time ago used as a food spices, for beverages and teas preparing, as well as therapeutics for digestive and respiratory diseases, were examined against human cervix adenocarcinoma HeLa, human melanoma Fem-x, human chronic myelogenous leukemia K562 and human breast adenocarcinoma MDA-MB-361 cells. MTT assay was used for determination of target cell survival. The most prominent cytotoxic effect was observed against K562 cells, especially by T. scordioides, T. montanum and T. botrys. All Teucrium extracts showed good cytotoxic activity on HeLa cells, but very low cytotoxic effect on MDA-MB-361 cells. In addition, the cytotoxic activities of T. scordioides and T. montanum extract were tested on healthy resting and phytohaemagglutinin-stimulated peripheral blood mononuclear cells (PHA-stimulated PBMC). T. scordioides and T. montanum extracts at concentration of 200 µg/ml reduced the resting PBMC and PHA-stimulated PBMC survival up to 10% and 20%, while the reduction of K562 cell survival at the same concentration of extracts was 94% and 97%, respectively. These results point to selectivity in their antitumor actions. Teucrium species can be regarded as promising candidates for natural plant sources of effective biological compounds as a supplements in the food industry, as well as for therapeutic use.

scholarly journals Xanthohumol, a Prenylated Flavonoid from Hops, Induces Caspase-Dependent Degradation of Oncoprotein BCR-ABL in K562 Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 402 ◽  
Author(s):  
Lu ◽  
Geng ◽  
Zhang ◽  
Miao ◽  
Liu
Keyword(s):  
Kinase Inhibitors ◽  
K562 Cells ◽  
Ubiquitin Proteasome System ◽  
Inhibitory Effect ◽  
Degradation Pathway ◽  
Myelogenous Leukemia ◽  
Phase Cell ◽  
Dependent Manner ◽  
Autophagy Induction ◽  
First Choice

BCR-ABL oncoprotein drives the initiation, promotion, and progression of chronic myelogenous leukemia (CML). Tyrosine kinase inhibitors are the first choice for CML therapy, however, BCR-ABL mediated drug resistance limits its clinical application and prognosis. A novel promising therapeutic strategy for CML therapy is to degrade BCR-ABL using small molecules. Antioxidant xanthohumol (XN) is a hop-derived prenylated flavonoid with multiple bioactivities. In this study, we showed XN could inhibit the proliferation, induce S phase cell cycle arrest, and stimulate apoptosis in K562 cells. XN degraded BCR-ABL in a concentration- and time-dependent manner, and the involved degradation pathway was caspase activation, while not autophagy induction or ubiquitin proteasome system (UPS) activation. Moreover, we revealed for the first time that XN could inhibit the UPS and autophagy in K562 cells, and the inhibitory effect of XN on autophagy could attenuate imatinib-induced autophagy and enhance the therapeutic efficiency of imatinib in K562 cells. Our present findings identified XN act as a degrader of BCR-ABL in K562 cells, and XN had potential to be developed as an alternate agent for CML therapy.

Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4219-4225 ◽  
Author(s):  
Tong Yin ◽  
Ying-Li Wu ◽  
Hui-Ping Sun ◽  
Guan-Lin Sun ◽  
Yan-Zhi Du ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Annexin V ◽  
K562 Cells ◽  
Inhibitory Effect ◽  
Mitochondrial Pathway ◽  
Myelogenous Leukemia ◽  
G1 Arrest ◽  
Activity Levels

Abstract Imatinib (STI571, Gleevec) is a tailored drug for chronic myelogenous leukemia (CML), whereas arsenic compounds were used as ancient remedies for CML with certain efficacy. The aim of this study was to investigate the potential benefit of combination therapy with imatinib and arsenic sulfide (As4S4). Analysis of cell proliferation and clonogenic ability showed that As4S4 and imatinib exerted synergistic effects on both K562 cells and fresh CML cells. The effective concentrations on fresh CML cells were pharmacokinetically available in vivo but had much less inhibitory effect on CD34+ cells from the nonleukemic donors. Examination of cell cycles showed that As4S4 induced G2/M arrest whereas imatinib induced G1 arrest. Using a number of parameters such as morphology, annexin V/propidium iodide (PI), mitochondrial transmembrane potential, caspase-3 activity, and Fas/Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through the mitochondrial pathway. The 2 drugs also exhibited a synergistic effect in targeting BCR-ABL protein. While As4S4 triggered its degradation and imatinib inhibited its tyrosine kinase activity, combined use of the 2 led to lower protein/enzymatic activity levels of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of imatinib and As4S4 combination on CML.

scholarly journals Semi-Synthesis of Harringtonolide Derivatives and Their Antiproliferative Activity

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1380
Author(s):  
Xiutao Wu ◽  
Lijie Gong ◽  
Chen Chen ◽  
Ye Tao ◽  
Wuxi Zhou ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Normal Cell ◽  
Selectivity Index ◽  
Cytotoxic Activities ◽  
Structure Activity ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Hct 116 ◽  
Systematic Structure

Harringtonolide (HO), a natural product isolated from Cephalotaxus harringtonia, exhibits potent antiproliferative activity. However, little information has been reported on the systematic structure−activity relationship (SAR) of HO derivatives. Modifications on tropone, lactone, and allyl positions of HO (1) were carried out to provide 17 derivatives (2–13, 11a–11f). The in vitro antiproliferative activity against four cancer cell lines (HCT-116, A375, A549, and Huh-7) and one normal cell line (L-02) was tested. Amongst these novel derivatives, compound 6 exhibited comparable cell growth inhibitory activity to HO and displayed better selectivity index (SI = 56.5) between Huh-7 and L-02 cells. The SAR results revealed that the tropone and lactone moieties are essential for the cytotoxic activities, which provided useful suggestions for further structural optimization of HO.

scholarly journals In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qun Zhang ◽  
Zengqiang Qu ◽  
Yanqing Zhou ◽  
Jin Zhou ◽  
Junwei Yang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Liver Microsomes ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Cytochrome P450 Enzymes ◽  
Drug Drug Interaction ◽  
Dose Dependent

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

scholarly journals SAT0363 DELPHINIDIN DOSE-DEPENDENTLY DIMINISHES PERIPHERAL IL-17 AND IFN-Γ PRODUCING LYMPHOCYTES IN PSORIATIC ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1128.1-1129
Author(s):  
A. Mavropoulos ◽  
S. Tsiogkas ◽  
D. Skyvalidas ◽  
C. Liaskos ◽  
A. Roussaki-Schulze ◽  
...  
Keyword(s):  
Psoriatic Arthritis ◽  
Cell Viability ◽  
Annexin V ◽  
Nkt Cells ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Research Support ◽  
Research Activities ◽  
Ifn Γ

Background:Delphinidin, a dietary anthocyanidin and powerful anti-oxidant from pigmented fruits and vegetables, has broad anti-inflammatory properties. In a human skin model of psoriasis, delphinidin reduced expression of proliferative and inflammatory markers (1).Objectives:The rationale of our study was to assess whether delphinidin can in vitro suppress IL-17 and IFN-γ production in peripheral blood mononuclear cell (PBMC) subsets from patients with psoriatic arthritis (PsA).Methods:PBMCs were obtained from 24 patients with PsA attending the outpatient clinic of the Department of Rheumatology/clinical Immunology at the University General Hospital of Larissa, Greece. 16 age- and sex-matched healthy volunteers were also included in the study. Delphinidin was supplemented at a concentration ranging from 1 to 50μg/ml, one hour prior to cell stimulation. Cell viability (Annexin V staining) and innate/adaptive lymphocyte subpopulations were assessed by flow cytometry with a panel of fluorochrome-conjugated antibodies against CD56, CD3, CD4 and CD8. Intracellular expression of IL-17 and IFN-γ was measured following PMA/ionomycin stimulation for 5 hours using standard cell permeabilization protocols and monoclonal antibodies against IL-17 and IFN-γResults:Delphinidin at concentration ≥10 μg/ml sharply diminished IL-17-production by CD4(+) T cells (Th17) and CD56(+)CD3(+) (NKT) cells from patients with psoriatic arthritis and normal controls (p≤0.05). IFN-γ producing T (CD4 and CD8) cells, as well as NK and NKT cells were also dose-dependently suppressed following delphinidin pre-incubation in both patients and healthy controls. Inhibition of IFN-γ(+) cells ranged from 27 to 69% and peaked at delphinidin concentration 20-50μg/ml. The inhibitory effect of delphinidin on IL-17 and IFN-γ producing lymphocytes was not due to compromised cell viability, as assessed by annexin V binding.Conclusion:Delphinidin exerts, in a dose-dependent manner, a profound in vitro inhibitory effect on T cell and NKT cell IL-17 and IFN-γ production in PsA, and therefore, it may be used as a dietary immunosuppressant, complementary to standard treatment.References:[1]Chamcheu JC Skin Pharmacol Physiol. 2015;28(4):177-88. doi: 10.1159/000368445Disclosure of Interests:ATHANASIOS MAVROPOULOS: None declared, Sotirios Tsiogkas: None declared, Dimitrios Skyvalidas: None declared, Christos Liaskos: None declared, Aggeliki Roussaki-Schulze Grant/research support from: Received a grant to support the educational and research activities of the department from Genesis Pharma (2018), Speakers bureau: Received honoraria from Genesis Pharma and Janssen(2017) and from Roche and Pharmaserve Lilly(2018), Efterpi Zafiriou Speakers bureau: Received honoraria from Genesis Pharma, Abbvie, Novartis, Roche, Jansses(2017) and Novartis, Abbvie(2018), Dimitrios Bogdanos: None declared, Lazaros Sakkas Grant/research support from: Received a grant to support the educational and research activities of the department from Bristol-Meyers Squib, Speakers bureau: Received honoraria from Actellion(2018), Janssen(2017), Novartis(2017), Sanofi-Aventis(2018), Abbvie(2017) and Roche(2017)

Synthesis and Characterization of New Palladium(II) Complexes with Ligands Derived from Furan-2-carbaldehyde and Benzaldehyde Thiosemicarbazone and their in vitro Cytotoxic Activities against Various Human Tumor Cell Lines

2010 ◽  
Vol 65 (10) ◽  
pp. 1271-1278 ◽  
Author(s):  
Wilfredo Hernández ◽  
Juan Paz ◽  
Fernando Carrasco ◽  
Abraham Vaisberg ◽  
Jorge Manzur ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Human Tumor ◽  
Myelogenous Leukemia ◽  
Cytotoxic Activities ◽  
Spectroscopic Techniques ◽  
Tumor Cell Lines ◽  
Human Tumor Cell ◽  
Human Tumor Cell Lines

With the ligands 4-phenyl-1-(furan-2-carbaldehyde)thiosemicarbazone, HTSC1, (1), 4-phenyl-1- (5´-phenyl-furan-2-carbaldehyde)thiosemicarbazone, HTSC2 (2), o-methoxy-benzaldehydethiosemicarbazone, HTSC3 (3), and o-cyano-benzaldehydethiosemicarbazone, HTSC4 (4), the corresponding palladium(II) complexes, Pd(TSC1)2 (5), Pd(TSC2)2 (6), Pd(TSC3)2 (7), and Pd(TSC4)2 (8) were synthesized and characterized by elemental analysis and spectroscopic techniques. The crystal structure of Pd(TSC3)2 (7) was determined by single-crystal X-ray diffraction. Complex 7 shows a squareplanar geometry, where two deprotonated ligands are coordinated to the PdII center through the nitrogen and sulfur atoms in a trans arrangement. In vitro antitumor studies against different human tumor cell lines have revealed that the palladium(II) complexes 5- 8 are more cytotoxic (IC50 values in the range of 0.21 - 3.79 μM) than their corresponding ligands (1 - 4) (> 60 μM). These results indicate that the antiproliferative activity is enhanced when thiosemicarbazone ligands are coordinated to the metal. Among the studied palladium(II) complexes, 8 exhibits high antitumor activity on K562 chronic myelogenous leukemia cells with a low value of the inhibitory concentration (IC50 = 0.21 μM).

Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: Inhibitory effect on endothelinA receptor—mediated contraction

2005 ◽  
Vol 102 (6) ◽  
pp. 1101-1107 ◽  
Author(s):  
Hartmut Vatter ◽  
Michael Zimmermann ◽  
Veronika Tesanovic ◽  
Andreas Raabe ◽  
Lothar Schilling ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Cerebral Vasospasm ◽  
Isometric Force ◽  
Inhibitory Effect ◽  
Affinity Constant ◽  
Dependent Manner ◽  
Content Type ◽  
The Right ◽  
Fine Print

Object. The central role of endothelin (ET)—1 in the development of cerebral vasospasm after subarachnoid hemorrhage is indicated by the successful treatment of this vasospasm in several animal models by using selective ETA receptor antagonists. Clazosentan is a selective ETA receptor antagonist that provides for the first time clinical proof that ET-1 is involved in the pathogenesis of cerebral vasospasm. The aim of the present investigation was, therefore, to define the pharmacological properties of clazosentan that affect ETA receptor—mediated contraction in the cerebrovasculature. Methods. Isometric force measurements were performed in rat basilar artery (BA) ring segments with (E+) and without (E−) endothelial function. Concentration effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 in the absence or presence of clazosentan (10−9, 10−8, and 10−7 M). The inhibitory potency of clazosentan was determined by the value of the affinity constant (pA2). The CECs for contraction induced by ET-1 and big ET-1 were shifted to the right in the presence of clazosentan in a parallel dose-dependent manner, which indicates competitive antagonism. The pA2 values for ET-1 were 7.8 (E+) and 8.6 (E−) and the corresponding values for big ET-1 were 8.6 (E+) and 8.3 (E−). Conclusions. The present data characterize clazosentan as a potent competitive antagonist of ETA receptor—mediated constriction of the cerebrovasculature by ET-1 and its precursor big ET-1. These functional data may also be used to define an in vitro profile of an ET receptor antagonist with a high probability of clinical efficacy.

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