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1.
Biochem Pharmacol ; 163: 308-320, 2019 05.
Article in English | MEDLINE | ID: mdl-30822403

ABSTRACT

Chronic myelogenous leukemia (CML) is clinically treated with imatinib, which inhibits the kinase activity of the Bcr-Abl oncoprotein. However, imatinib resistance remains a common clinical issue. Andrographolide, the major compound of the medicinal plant Andrographis paniculata, was reported to exhibit anticancer activity. In this study, we explored the therapeutic potential of andrographolide and its derivative, NCTU-322, against both imatinib-sensitive and imatinib-resistant human CML cell lines. Both andrographolide and NCTU-322 downregulated the Bcr-Abl oncoprotein in imatinib-resistant CML cells through an Hsp90-dependent mechanism similar to that observed in imatinib-sensitive CML cells. In addition, NCTU-322 had stronger effects than andrographolide on downregulation of Bcr-Abl oncoprotein, induction of Hsp90 cleavage and cytotoxicity of CML cells. Notably, andrographolide and NCTU-322 could induce differentiation, mitotic arrest and apoptosis of both imatinib-sensitive and imatinib-resistant CML cells. Finally, the anticancer activity of NCTU-322 against imatinib-resistant CML cells was demonstrated in vivo. In summary, our data demonstrated that andrographolide and NCTU-322 inhibit Bcr-abl function via a mechanism different from that of imatinib, and they induced multiple anticancer effects in both imatinib-sensitive and resistant CML cells. Our findings demonstrate that andrographolide and NCTU-322 are potential therapeutic agents again CML.


Subject(s)
Antineoplastic Agents/pharmacology , Diterpenes/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Genes, abl/physiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Diterpenes/chemistry , Drug Resistance, Neoplasm , Genes, abl/genetics , Humans , Imatinib Mesylate/pharmacology , Leukocytes, Mononuclear/drug effects , Molecular Structure
2.
Eur J Pharmacol ; 812: 113-120, 2017 Oct 05.
Article in English | MEDLINE | ID: mdl-28694068

ABSTRACT

Con A-induced hepatitis in mice is an established model of autoimmune hepatitis (AIH). JKB-122, a toll-like receptor 4 (TLR4) antagonist, was tested for hepatotprotectant activity. Within several hours of Con A challenge (15mg/kg iv), increased production of proinflammatory cytokines with inflammatory infiltrate occurred in the liver. The severity of tissue necrosis and the amount of circulating liver enzymes peak at 24h post Con A challenge. JKB-122 was given 24 and 16h before, then concurrently, and 4 and 8h (× 5 doses) after challenge with Con A. Serum and liver were harvested at 3, 9 and 24h post Con A challenge. JKB-122 at 20 and 50mg/kg po prevented the increase of serum liver enzymes by 47% and 95% respectively vs vehicle control 24h post Con A. JKB-122 significantly inhibited Con A-induced pathological lesions in the liver and the amount of IFN-γ IL-1ß, IL-4, IL-5, IL-6, IL-17A and TNF-α starting as early as 3h post Con A. Moreover, JKB-122 given concurrently (× 3 doses) with Con A showed similar effect. Finally, JKB-122 enhanced the therapeutic effects of submaximal dose of prednisolone with improved lesion score. It is concluded that JKB-122 at 20 and 50mg/kg po caused dose-dependent inhibition of elevated liver enzymes in Con A-induced hepatitis in mice, indicating hepatoprotectant activity. The results suggest that JKB-122 as monotherapy or in combination with prednisolone may offer a viable approach to the treatment of AIH.


Subject(s)
Concanavalin A/adverse effects , Hepatitis/drug therapy , Hepatitis/etiology , Organic Chemicals/pharmacology , Prednisolone/pharmacology , Animals , Cytokines/metabolism , Cytoprotection/drug effects , Dose-Response Relationship, Drug , Drug Interactions , Hepatitis/metabolism , Hepatitis/pathology , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred BALB C , Organic Chemicals/therapeutic use , Toll-Like Receptor 4/antagonists & inhibitors
3.
PLoS One ; 11(4): e0152770, 2016.
Article in English | MEDLINE | ID: mdl-27035713

ABSTRACT

Andrographolide (ANDRO) is a lactone diterpenoid compound present in the medicinal plant Andrographis paniculata which is clinically applied for multiple human diseases in Asia and Europe. The pharmacological activities of andrographolide have been widely demonstrated, including anti-inflammation, anti-cancer and hepatoprotection. However, the pharmacological mechanism of andrographolide remains unclear. Therefore, further characterization on the kinetics and molecular targets of andrographolide is essential. In this study, we described the synthesis and characterization of a novel fluorescent andrographolide derivative (ANDRO-NBD). ANDRO-NBD exhibited a comparable anti-cancer spectrum to andrographolide: ANDRO-NBD was cytotoxic to various types of cancer cells and suppressed the migration activity of melanoma cells; ANDRO-NBD treatment induced the cleavage of heat shock protein 90 (Hsp90) and the downregulation of its client oncoproteins, v-Src and Bcr-abl. Notably, ANDRO-NBD showed superior inhibitory effects to andrographolide in all anticancer assays we have performed. In addition, ANDRO-NBD was further used as a fluorescent probe to investigate the uptake kinetics, cellular distribution and molecular targets of andrographolide. Our data revealed that ANDRO-NBD entered cells rapidly and its fluorescent signal could be detected in nucleus, cytoplasm, mitochondria, and lysosome. Moreover, we demonstrated that ANDRO-NBD was covalently bound to several putative target proteins of andrographolide, including NF-κB and hnRNPK. In summary, we developed a fluorescent andrographolide probe with comparable bioactivity to andrographolide, which serves as a powerful tool to explore the pharmacological mechanism of andrographolide.


Subject(s)
Diterpenes/chemistry , Molecular Probes/chemistry , Adult , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged
4.
Oncotarget ; 7(10): 11677-86, 2016 Mar 08.
Article in English | MEDLINE | ID: mdl-26883191

ABSTRACT

CCL-34, a synthetic α-galactosylceramide analog, has been reported as an activator of toll-like receptor 4 (TLR4) in macrophages. TLR4 is highly expressed in dendritic cell (DC) and several TLR4 agonists are known to trigger DC maturation. We herein evaluated the effect of CCL-34 on DC maturation. Human CD14+ monocyte-derived immature DC were treated with CCL-34, its inactive structural analog CCL-44, or LPS to assess the DC maturation. CCL-34 induced DC maturation according to their characteristically dendrite-forming morphology, CD83 expression and IL-12p70 production. The allostimulatory activity of DC on proliferation of naive CD4+CD45+RA+ T cells and their secretion of interferon-γ was increased by CCL-34. Phagocytosis, an important function of immature DC, was reduced after CCL-34 treatment. All these effects related to DC maturation were evidently induced by positive control LPS but not by CCL-44 treatment. TLR4 neutralization impaired human DC maturation triggered by CCL-34. The induction of IL-12, a hallmark of DC maturation, by CCL-34 and LPS was only evident in TLR4-competent C3H/HeN, but not in TLR4-defective C3H/HeJ mice. CCL-34 could further elicit the antigen presentation capability in mice inoculated with doxorubicin-treated colorectal cancer cells. In summary, CCL-34 triggers DC maturation via a TLR4-dependent manner, which supports its potential application as an immunostimulator.


Subject(s)
Dendritic Cells/drug effects , Glycolipids/pharmacology , Myeloid Cells/drug effects , Serine/analogs & derivatives , Animals , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Dendritic Cells/cytology , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Myeloid Cells/cytology , Serine/pharmacology , Signal Transduction/drug effects
5.
Biochem Pharmacol ; 87(2): 229-42, 2014 Jan 15.
Article in English | MEDLINE | ID: mdl-24161787

ABSTRACT

Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90α was identified in andrographolide-treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Diterpenes/pharmacology , Genes, abl/physiology , Genes, src/physiology , HSP90 Heat-Shock Proteins/metabolism , Reactive Oxygen Species/metabolism , Amino Acid Sequence , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Diterpenes/therapeutic use , Down-Regulation/drug effects , Down-Regulation/physiology , Genes, abl/drug effects , Genes, src/drug effects , HSP90 Heat-Shock Proteins/genetics , Humans , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Molecular Sequence Data
6.
J Agric Food Chem ; 58(20): 10831-9, 2010 Oct 27.
Article in English | MEDLINE | ID: mdl-20923145

ABSTRACT

Macrophages and dendritic cells are required for initiating innate immunity and adaptive immunity. Aberrant activation of macrophages and dendritic cells can cause detrimental immune responses; thus, agents effectively modulating their functions are of great clinical value. We herein investigated whether fisetin, a flavonoid prevalently present in fruits and vegetables, could inhibit macrophage activation and dendritic cell maturation. Fisetin suppressed LPS-induced NF-κB activation, expression of pro-inflammatory proteins (TNF-α and iNOS), MMP-9 activity, and phagocytic activity in macrophages. Furthermore, upon LPS-induced dendritic cell maturation, fisetin at nontoxic concentrations suppressed the expression of costimulatory molecules (CD80 and CD86), the production of cytokines (IL-12, IL-6, and TNF-α), and the endocytic activity of dendritic cells. Fisetin treatment significantly attenuated migration of dendritic cells into spleens and dendritic cell-mediated T cell activation in LPS-treated mice. Collectively, our data reveal that fisetin inhibits macrophage activation and impairs functional maturation of dendritic cells.


Subject(s)
Dendritic Cells/drug effects , Flavonoids/pharmacology , Lipopolysaccharides/immunology , Macrophage Activation/drug effects , Macrophages/drug effects , Plant Extracts/pharmacology , Animals , Cells, Cultured , Dendritic Cells/immunology , Down-Regulation/drug effects , Flavonols , Macrophages/immunology , Mice , Mice, Inbred C3H
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