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1.
Food Chem Toxicol ; 59: 572-8, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23845509

ABSTRACT

(R)-(+)-Goniothalamin (GTN), a styryl-lactone isolated from the medicinal plant Goniothalamus macrophyllus, exhibits pharmacological activities including cytotoxic and anti-inflammatory effects. In this study, GTN modulated TNF-α induced NF-κB activation. GTN concentrations up to 20 µM showed low cytotoxic effects in K562 chronic myelogenous leukemia and in Jurkat T cells. Importantly, at these concentrations, no cytotoxicity was observed in healthy peripheral blood mononuclear cells. Our results confirmed that GTN inhibited tumor necrosis factor-α (TNF-α)-induced NF-κB activation in Jurkat and K562 leukemia cells at concentrations as low as 5 µM as shown by reporter gene assays and western blots. Moreover, GTN down-regulated translocation of the p50/p65 heterodimer to the nucleus, prevented binding of NF-κB to its DNA response element and reduced TNF-α-activated interleukin-8 (IL-8) expression. In conclusion, GTN inhibits TNF-α-induced NF-κB activation at non-apoptogenic concentrations in different leukemia cell models without presenting toxicity towards healthy blood cells underlining the anti-leukemic potential of this natural compound.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Drug Discovery , Leukemia/drug therapy , NF-kappa B/metabolism , Pyrones/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cells, Cultured , Genes, Reporter/drug effects , Goniothalamus/chemistry , Humans , Interleukin-8/antagonists & inhibitors , Interleukin-8/metabolism , Jurkat Cells , K562 Cells , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Malaysia , NF-kappa B/agonists , NF-kappa B/antagonists & inhibitors , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Plant Roots/chemistry , Protein Transport/drug effects , Pyrones/adverse effects , Pyrones/isolation & purification , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Response Elements/drug effects , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
3.
Biochem Pharmacol ; 81(1): 13-23, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-20849830

ABSTRACT

Cardiac steroids are used to treat various diseases including congestive heart failure and cancer. The aim of this study was to investigate the anti-leukemic activity of UNBS1450, a hemi-synthetic cardenolide belonging to the cardiac steroid glycoside family. Here, we report that, at low nanomolar concentrations, UNBS1450 induces apoptotic cell death. Subsequently, we have investigated the molecular mechanisms leading to apoptosis activation. Our results show that UNBS1450 inhibits NF-κB transactivation and triggers apoptosis by cleavage of pro-caspases 8, 9 and 3/7, by decreasing expression of anti-apoptotic Mcl-1 and by recruitment of pro-apoptotic Bak and Bax protein eventually resulting in cell death.


Subject(s)
Apoptosis/drug effects , Cardenolides/pharmacology , Leukemia/drug therapy , Cardenolides/chemistry , Cell Line , Gene Expression Regulation, Neoplastic , Humans , Molecular Structure , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism
4.
Ann N Y Acad Sci ; 1171: 436-47, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19723087

ABSTRACT

Curcumin, a natural product isolated from the plant Curcuma longa, has a diverse range of molecular targets that influence numerous biochemical and molecular cascades. Curcumin has been shown to inhibit nuclear factor kappaB (NF-kappaB) activation at several steps in the NF-kappaB signaling pathways and thereby controls numerous NF-kappaB-regulated genes involved in various diseases. In the present study, we investigated the effect of curcumin pretreatment on 84 tumor necrosis factor-alpha (TNF-alpha)-activated genes of NF-kappaB pathways in K562 cells, using a real-time PCR array. Our results show that transcription of 29 NF-kappaB-related mRNAs was significantly downregulated (CARD4, CCL2, CD40, CSF2, F2R, ICAM1, IKBKB, IKBKE, IL1A, IL1B, IL6, IL8, IRAK2, MALT1, MAP3K1, MYD88, NFKB1, NFKB2, NFKBIA, PPM1A, RAF1, RELB, STAT1, TLR3, TNF, TNFalphaIP3, TNFSF10, and TICAM1), whereas 10 mRNAs were induced (AGT, CASP1, CSF3, FOS, IFNG, IL10, TICAM2, TLR2, TLR9, and TNFRSF7). Western blot analysis of CD40, NFKB1 (p50), RELB, NFKBIA (IkappaBalpha), and IL10 as well as an IL8 secretion assay confirmed our results. Taken together, we show that curcumin regulates an impressive number of NF-kappaB genes within the different NF-kappaB signaling pathways.


Subject(s)
Curcumin/pharmacology , Gene Expression Regulation, Leukemic/genetics , NF-kappa B/metabolism , Signal Transduction/genetics , Antineoplastic Agents/pharmacology , Blotting, Western , CD40 Antigens/metabolism , Enzyme-Linked Immunosorbent Assay/methods , Humans , Interleukin-10/metabolism , Interleukin-8/metabolism , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , NF-kappa B p50 Subunit/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factor RelB/metabolism , Tumor Necrosis Factor-alpha/pharmacology
5.
Biochem Pharmacol ; 78(1): 1-10, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19447218

ABSTRACT

Despite significant progress in oncology therapeutics in the last decades, the urge to discover and to develop new, alternative or synergistic anti-cancer agents still remains. For centuries it has been known that the coarse shrub Calotropis procera is a very promising source of ascaricidal, schizonticidal, anti-bacterial, anthelmintic, insecticidal, anti-inflammatory, anti-diarrhoeal, larvicidal and cytotoxic chemicals. Different compounds like norditerpenic esters, organic carbonates, the cysteine protease procerain, alkaloids, flavonoids, sterols as well as numerous types of cardenolides have provided this plant for centuries with scientists' interest. The chemical class of cardenolides and their related bioactivity evaluation and structure-activity relationship (SAR) studies pointed out their therapeutic utility and led to the discovery of promising drug candidates. Recently the cardiotonic steroid UNBS1450 01 (derived from 2-oxovoruscharin 02) from C. procera was shown to additionally exert an anti-cancer activity. UNBS1450 01 has been proven to be a potent sodium pump inhibitor, showing anti-proliferative and cell death-inducing activities. This anti-cancer potential of UNBS1450 01 is achieved by disorganization of the actin cytoskeleton after binding to the sodium pump at the cellular membrane, by inducing autophagy-related cell death, by repressing NF-kappaB activation as well as by down-regulating c-Myc in cancer cells. We aim to review pharmacologically important chemical extracts from C. procera and focus more specifically on the anti-cancer activities of UNBS1450 01.


Subject(s)
Calotropis/cytology , Calotropis/physiology , Cardenolides/therapeutic use , Cell Death/physiology , Signal Transduction/physiology , Calotropis/enzymology , Cardenolides/isolation & purification , Cardenolides/metabolism , Cardiac Glycosides/isolation & purification , Cardiac Glycosides/therapeutic use , Cell Division , Plant Extracts/isolation & purification , Plant Extracts/therapeutic use , Signal Transduction/drug effects , Sodium-Potassium-Exchanging ATPase/isolation & purification , Sodium-Potassium-Exchanging ATPase/metabolism , Structure-Activity Relationship
6.
J Immunol ; 182(8): 5088-97, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19342689

ABSTRACT

MicroRNAs (miRNAs) have emerged as key players in the regulation of expression of target mRNAs expression. They have been associated with diverse biological processes, and recent studies have demonstrated that miRNAs play a role in inflammatory responses. We reported previously that LPS-activated fibroblast-like synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients express IL-18 mRNA but they do not release IL-18. Based on the observation that this inhibition was due to a rapid degradation of IL-18 mRNA, our group has conducted a study to identify miRNAs that could play a role in the "antiinflammatory" response of LPS-activated RA FLS. LPS challenge modulated the expression of 63 miRNAs as assessed by microarray analysis. Fifteen miRNAs were up-regulated, including miR-346, for which overexpression upon LPS treatment was validated by quantitative RT-PCR. We then transfected FLS with an antisense oligonucleotide targeting miR-346 and found that, in these conditions, IL-18 release could be measured upon LPS activation of FLS. Moreover, we also demonstrated that miR-346 indirectly regulated IL-18 release by indirectly inhibiting LPS-induced Bruton's tyrosine kinase expression in LPS-activated RA FLS. These findings suggest that miRNAs function as regulators that help to fine-tune the inflammatory response in RA.


Subject(s)
Arthritis, Rheumatoid/metabolism , Gene Expression Regulation/genetics , Interleukin-18/metabolism , Lipopolysaccharides/pharmacology , MicroRNAs/genetics , Protein-Tyrosine Kinases/metabolism , Synovial Membrane/metabolism , Agammaglobulinaemia Tyrosine Kinase , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/genetics , Base Sequence , Cell Line , Cells, Cultured , Humans , Interleukin-18/biosynthesis , Interleukin-18/genetics , Oligonucleotide Array Sequence Analysis , Protein-Tyrosine Kinases/genetics , RNA Interference , RNA, Messenger/genetics , Synovial Membrane/drug effects
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