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The proteasomal 19S regulatory particle (RP) associated deubiquitinases (DUBs) have attracted much attention owing to their potential as a therapeutic target for cancer therapy. Identification of new entities against 19S RP associated DUBs and illustration of the underlying mechanisms is crucial for discovery of novel proteasome blockers. In this study, a series of 4-arylidene curcumin analogues were identified as potent proteasome inhibitor by preferentially blocking deubiquitinase function of proteasomal 19S RP with moderate 20S CP inhibition. The most active compound 33 exhibited a major inhibitory effect on 19S RP-associated ubiquitin-specific proteases 14, along with a minor effect on ubiquitin C-terminal hydrolase 5, which resulted in dysfunction of proteasome, and subsequently accumulated ubiquitinated proteins (such as IκB) in several cancer cells. Remarkably, though both 19S RP and 20S CP inhibition induced significantly endoplasmic reticulum stress and triggered caspase-12/9 pathway activation to promote cancer cell apoptosis, the 19S RP inhibition by 33 avoided slow onset time, Bcl-2 overexpression, and PERK-phosphorylation, which contribute to the deficiencies of clinical drug Bortezomib. These systematic studies provided insights in the development of novel proteasome inhibitors for cancer treatment. [ABSTRACT FROM AUTHOR]

A highly specific fluorescent probe (OC9) was discovered exhibiting tubulin-specific affinity fluorescence, which allowed selective labeling of cellular tubulin in microtubules. Moreover, distinct tubulin dynamics in various cellular bio-settings such as drug resistant or epithelial-mesenchymal transition (EMT) cancer cells were directly observed for the first time via OC9 staining. [ABSTRACT FROM AUTHOR]

A seriesof new ortho-aryl chalcones have been designed and synthesized.Many of these compounds were found to exhibit significant antiproliferationactivity toward a panel of cancer cell lines. Selected compounds showpotent cytotoxicity against several drug resistant cell lines includingpaclitaxel (Taxol) resistant human ovarian carcinoma cells, vincristineresistant human ileocecum carcinoma cells, and doxorubicin resistanthuman breast carcinoma cells. Further investigation revealed thatactive analogues could inhibit the microtubule polymerization by bindingto colchicine site and thus induce multipolar mitosis, G2/M phase arrest, and apoptosis of cancer cells. Furthermore, affinity-basedfluorescence enhancement was observed during the binding of activecompounds with tubulin, which greatly facilitated the determinationof tubulin binding site of the compounds. Finally, selected compound 26was found to exhibit obvious in vivo antitumor activityin A549 tumor xenografts model. Our systematicstudies implied a new scaffold targeting tubulin and mitosis for novelantitumor drug discovery. [ABSTRACT FROM AUTHOR]

Abstract: A series of new 4-arylidene curcumin analogues (4-arylidene-1,7-bisarylhepta-1,6-diene-3,5-diones) were synthesized and found to be potent antiproliferative agents against a panel of cancer cell lines at submicromolar to low micromolar concentrations by SRB assay. Their inhibitory abilities against NF-κB was evaluated by High Content Analysis (HCA) based immunofluorescence assay; and the Akt signalling inhibition was determined by fluorescence polarization assay and western blot respectively. The Structure–Activity Relationship was discussed. Our results revealed that 4-arylidene curcumin analogues may work in a multi-targets manner in cancer cell. [Copyright &y& Elsevier]

Abstract: A series of biaryl-based chalcones were designed as a combination of the natural chalcone and biphenyl moieties, and synthesized by two step chemistry involving Knoevenagel reaction and microwave assistant Suzuki coupling. Sulforhodamine B (SRB) assay was performed to evaluate the cell viability inhibitory abilities of these compounds against five cancer cell lines (A549, CNE2, SW480, MCF-7, and HepG2) from different tissues. Their Nuclear Factor-κB (NF-κB) nuclear translocation inhibitory activities were further investigated by High Content Analysis (HCA) based assay. Most of the compounds showed moderate to strong anticancer and NF-κB nuclear translocation inhibition activities and potent compounds were found. [Copyright &y& Elsevier]

A variety of biaryl-based chalcones are designed, synthesized and evaluated for their inhibitory activities against five cancer cell lines. [ABSTRACT FROM AUTHOR]

Abstract: (1E,4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(5-methylfuran-2-yl)hepta-1,4,6-trien-3-one (2a), a novel curcumin analog, was previously synthesized in our laboratory as a potential thioredoxin reductase (TrxR) inhibitor with excellent growth inhibitory effects on several TrxR over-expressed cancer cells. In this study, our further studies show that 2a is able to inhibit the growth of cisplatin-resistant A549 (A549/CDDP) cells much more effectively in a dose-dependent manner than that of A549 cells in antiproliferative activity experiments. Moreover, 2a-pretreated A549/CDDP cells are sensitive to cisplatin treatment, which is accompanied by the inhibition of TrxR activity in A549/CDDP cells. As a consequence of targeting TrxR, 2a in turn remarkably up-regulates intracellular reactive oxygen species level, depletes glutathione (GSH), and reduces the GSH/GSSG ratio, suggesting that the intracellular redox balance is shifted to a more oxidative state. Consequently, concomitant with the cell growth inhibition of 2a, apoptosis is induced by 2a probably through increased oxidative stress in A549/CDDP cells. In conclusion, these observations demonstrated that TrxR inhibitors would be promising drugs to achieve a successful combinatory or single cancer chemotherapy. [Copyright &y& Elsevier]

Factor Xa (FXa) is a serine protease that plays key roles in linking the intrinsic and extrinsic coagulation pathways to the final common pathway. DJT06001 is an oral, highly specific and direct FXa inhibitor for the prevention and treatment of thromboembolic diseases. We characterized the compound in vitro and studied its in vivo activity in rat thrombosis models, as well as bleeding risk and Pharmacokinetics and Pharmacodynamics (PK/PD) relationship. DJT06001 inhibited free FXa with an inhibitory constant (Ki) of 0.99 nM, and exhibited >10000-fold selectivity for FXa than for other related serine proteases. DJT06001 concentration-dependently inhibited FXa activity in the prothrombinase complex with an IC 50 of 2.53 nM. The concentrations for DJT06001 to double the prothrombin time (PT) and activated partial thromboplastin time (APTT) were 0.74 and 0.57 μM, respectively. Importantly, DJT06001 did not impair platelet aggregation induced by ADP, platelet activating factor (PAF) and collagen. Furthermore, DJT06001 inhibited thrombus formation in rat thrombosis models in a dose dependent manner. And in rat tail bleeding risk test, it caused less bleeding than rivaroxaban at doses that achieve the same antithrombotic effect. PK/PD studies further demonstrated that there was a good correlation between the plasma concentrations of DJT06001and its inhibition of plasma FXa activity and prolongation of PT. In conclusion, DJT06001 was shown to be a potent and specific FXa inhibitor with excellent PK/PD profiles and it could be developed as a new anticoagulant for the management of thromboembolic diseases. [ABSTRACT FROM AUTHOR]

(E)−1-(3′-fluoro-[1,1′-biphenyl-3-yl)−3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one) ( MC37 ), a novel mono-carbonyl curcumin analog, was previously synthesized in our laboratory as a nuclear factor kappa B (NF- κ B) inhibitor with excellent cytotoxicity against several cancer cell lines. In this study, our further investigations showed that the potent growth inhibitory activity of MC37 in human colorectal cancer cells was associated with the arrest of cell cycle progression and the induction of apoptosis. As a multi-targeted agent, MC37 inhibited the intracellular microtubule assembly, altered the expression of cyclin-dependent kinase 1 (CDK1), and ultimately induced G2/M cell cycle arrest. Moreover, MC37 collapsed the mitochondrial membrane potential (MMP), increased the Bax/Bcl-2 ratio, activated the caspase-9/3 cascade, and finally led to cancer cells apoptosis, suggesting that the mitochondrial-mediated apoptotic pathway was involved in MC37 -induced apoptosis. In conclusion, these observations demonstrated that mono-carbonyl curcumin analogs would serve as multi-targeted lead for promising anti-colorectal cancer agent development. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy that is most common in East Asia, Africa, and Alaska. Radiotherapy is the main treatment option; unfortunately, disease response to concurrent radiotherapy and chemotherapy varies among patients with NPC, and in many cases, NPC becomes resistant to radiotherapy. Our previous studies indicated that Jab1/CSN5 was overexpressed and plays a role in the pathogenesis and radiotherapy resistance in NPC. Therefore, it is important to seek for innovative therapeutics targeting Jab1/CSN5 for NPC. In this study, we explored the antitumor effect of a curcumin analogue T83 in NPC, and found T83 exhibits antitumor activity and induces radiosensitivity through inactivation of Jab1 in NPC.Methods: NPC cell viability and proliferation were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. Cell cycle distribution was detected with use of flow cytometry. Apoptosis was examined by using the Annexin V/propidium iodide staining assay and cleavage poly(ADP-ribose polymerase (PARP) and cleavage caspase-3 expression. Jab1 expression was examined by Western blotting.Results: A growth inhibitory effect was observed with T83 treatment in a dose- and time-dependent manner. T83 significantly induced G2/M arrest and apoptosis in NPC. In addition, T83 inhibited Jab1 expression and sensitized NPC cells to radiotherapy.Conclusion: Our data indicate that T83 exhibits potent inhibitory activity in NPC cells and induces radiotherapy sensitivity. Thus, T83 has translational potential as a chemopreventive or therapeutic agent for NPC. [ABSTRACT FROM AUTHOR]