Synthesis and Identification of New 4-Arylidene Curcumin Analogues as Potential Anticancer Agents Targeting Nuclear Factor-κB Signaling Pathway.
ABSTRACT A series of curcumin analogues including new 4-arylidene curcumin analogues (4-arylidene-1,7-bisarylhepta-1,6-diene-3,5-diones) were synthesized. Cell growth inhibition assays revealed that most 4-arylidene curcumin analogues can effectively decrease the growth of a panel of lung cancer cells at submicromolar and low micromolar concentrations. High content analysis technology coupled with biochemical studies showed that this new class of 4-arylidene curcumin analogues exhibits significantly improved NF-κB inhibition activity over the parent compound curcumin, at least in part by inhibiting IκB phosphorylation and degradation via IKK blockage; selected 4-arylidene curcumin analogues also reduced the tumorigenic potential of cancer cells in a clonogenic assay.
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ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and in spite of intense efforts there are limited therapeutic options for patients with PDAC. PDACs harbor a high frequency of Kras mutations and other driver mutations that lead to altered signaling pathways and contribute to therapeutic resistance. Importantly, constitutive activation of nuclear factor κB (NF-κB) is frequently observed in PDAC. An increasing body of evidence suggests that both classical and non-classical NF-κB pathways play a crucial role in PDAC development and progression. In this review, we update the most recent advances regarding different aspects of NF-κB involvement in PDAC development and progression, emphasizing its potential as a therapeutic target and the need to discover pathway-specific cytosolic NF-κB regulators which could be used to design novel therapeutic strategies for PDAC.Oncotarget 11/2014; · 6.63 Impact Factor
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ABSTRACT: Among polymeric nanoparticles designed for cancer therapy, PLGA nanoparticles have become one of the most popular polymeric devices for chemotherapeutic based-nanoformulations against several kinds of malignant diseases. Promising properties, including long-circulation time, enhanced tumor localization, interference with "multidrug" resistance effects and environmental biodegradability, often result in an improvement of the drug bioavailability and effectiveness. In the present work, we have synthesized 1,7-Bis-(3,4-dimethoxy-phenyl)-5-hydroxy-hepta-1,4,6-trien-3-one (ASC-J9) and developed uniform ASC-J9-loaded PLGA nanoparticles of about 120 nm in size, which have been prepared by a single-emulsion process. Structural and morphological features of the nanoformulation were analyzed, followed by an accurate evaluation of the in vitro drug release kinetics, which exhibited Fickian-law diffusion over 10 days. The intracellular degradation of ASC-J9-bearing nanoparticles within estrogen-dependent MCF-7 breast cancer cells was correlated to a time- and dose-dependent activity of the released drug. A cellular growth inhibition associated with a specific cell cycle G2/M blocking effect caused by ASC-J9 release inside the cytosol allowed us to put forward an hypothesis on the action mechanism of this nanosystem, which led to the final cell apoptosis. Our study was accomplished using Annexin V-based cell death analysis, MTT assessment of proliferation, radical scavenging activity and intracellular ROS evaluation. Moreover, the intracellular localization of nanoformulated ASC-J9 was confirmed by a Raman optical imaging experiment designed ad hoc. Eventually, PLGA nanoparticles and ASC-J9 proved also to be safe for a healthy embryo fibroblasts cell line (3T3-L1), suggesting a possible clinical translation of this potential nanochemotherapeutic to expand the inherently poor bioavailability of hydrophobic ASC-J9 that could be proposed for the treatment of malignant breast cancer.Molecular Pharmaceutics 06/2014; · 4.79 Impact Factor
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ABSTRACT: Here, we report studies on the antioxidant activity and redox behavior of curcumin and its structurally modified synthetic analogues. We have synthesized a number of analogues of curcumin which abrogate its keto-enol tautomerism or substitute the methylene group at the centre of its heptadione moiety implicated in the hydride transfer and studied their redox property. From cyclic voltammetric studies, it is demonstrated that H- atom transfer from CH2 group at the center of the heptadione link also plays an important role in the antioxidant properties of curcumin along with that of its phenolic–OH group. In addition, we also show that the conversion of 1, 3- dicarbonyl moiety of curcumin to an isosteric heterocycle as in pyrazole curcumin, which decreases its rotational freedom, leads to an improvement of its redox properties as well as its antioxidant activityElectrochimica Acta 01/2015; 151:574. · 4.09 Impact Factor