Chrysanthemum indicum L. Extract Induces Apoptosis through Suppression of Constitutive STAT3 Activation in Human Prostate Cancer DU145 Cells
ABSTRACT Chrysanthemum indicum L. has been shown to possess antiinflammatory and anticancer activities, but its molecular targets/pathways are not yet fully understood in tumor cells. In the present study, the potential effects of C. indicum on signal transducer and activator of transcription 3 (STAT3) signaling pathway in different tumor cells were examined. The solvent fractions (hexane, CH(2) Cl(2) , EtOAc, and BuOH,) were obtained from a crude extract (80% EOH extract) of C. indicum. The methylene chloride fraction of C. indicum (MCI) exhibited strong cytotoxic activity as compared with the other fractions and clearly suppressed constitutive STAT3 activation against both DU145 and U266 cells, but not MDA-MB-231 cells. The suppression of constitutive STAT3 activation by MCI is associated with blocking upstream JAK1 and JAK2, but not Src. MCI downregulated the expression of STAT3-regulated gene products; this is correlated with the accumulation of the cell cycle at sub-G1 phase, the induction of caspase-3 activation, and apoptosis. Moreover, the major components of the MCI were bioactive compounds such as sudachitin, hesperetin, chrysoeriol, and acacetin. Sudachitin, chrysoeriol, and acacetin also exerted significantly cytotoxicity, clearly suppressed constitutive STAT3 activation, and induced apoptosis, although hesperetin did not show any significant effect in DU145 cells. Overall, our results demonstrate that MCI could induce apoptosis through inhibition of the JAK1/2 and STAT3 signaling pathways. Copyright © 2012 John Wiley & Sons, Ltd.
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ABSTRACT: The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are targeted by a therapeutic regimen. In the present review, we provide an update on the molecular pathways that play an important role in the pathogenesis of CRPC and discuss the current wave of new treatments to combat this lethal disease.Biologics: Targets & Therapy 08/2012; 6:267-76. DOI:10.2147/BTT.S23954
Article: Bioactive acetylenic metabolites[Show abstract] [Hide abstract]
ABSTRACT: This article focuses on anticancer, and other biological activities of acetylenic metabolites obtained from plants and fungi. Acetylenic compounds belong to a class of molecules containing triple bond(s). Naturally occurring acetylenics are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifungal, and immunosuppressive properties. There are of great interest for medicine, pharmacology, medicinal chemistry, and pharmaceutical industries. This review presents structures and describes cytotoxic activities of more than 100 acetylenic metabolites, including fatty alcohols, ketones, and acids, acetylenic cyclohexanoids, spiroketal enol ethers, and carotenoids isolated from fungi and plants.Phytomedicine: international journal of phytotherapy and phytopharmacology 07/2013; 20(13). DOI:10.1016/j.phymed.2013.06.009 · 3.13 Impact Factor
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ABSTRACT: The purpose of this study was to investigate whether the kappa-opioid receptor (KOR) agonist, BRL52537, has a neuroprotective effect against cerebral ischemia/reperfusion (I/R) injury in rats and further explore the underlying mechanisms. Adult male Sprague-Dawley rats were randomly assigned into sham (group A), I/R (group B), BRL52537 (KOR agonist) + I/R (group C), nor-BNI (nor-binaltorphimine, KOR antagonist) + I/R (group D), AG490 (STAT3 phosphorylation inhibitor) + I/R (group E), dimethyl sulfoxide (DMSO, vehicle of AG490) + I/R (group F), and BRL52537 + AG490 +I/R (group G) groups. Cerebral I/R injury was induced by 10 min exposure to global ischemia (4-VO). Histopathological changes and neuronal apoptosis were evaluated with H&E staining and the TUNEL assay, respectively. Expression levels of signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 and caspase-3 were determined with western blot analysis. Our results showed that BRL52537 protects against I/R injury-induced brain damage and inhibits neuronal apoptosis to a significant extent. Additionally, BRL52537 promoted up-regulation of p-STAT3 and a marked decrease in caspase-3 expression. Based on the collective findings, we propose that the KOR agonist, BRL52537, protects against cerebral I/R injury via a mechanism involving STAT3 signaling.Neurochemical Research 08/2013; 38(11). DOI:10.1007/s11064-013-1139-4 · 2.59 Impact Factor