Powerful tumor cell growth-inhibiting activity of a synthetic derivative of atractyligenin: Involvement of PI3K/Akt pathway and thioredoxin system

Cotugno, Roberta; Gallotta, Dario; Piaz, Fabrizio Dal; Apicella, Ivana; Falco, Sandro De; Rosselli, Sergio; Bruno, Maurizio; Belisario, Maria Antonietta

doi:10.1016/j.bbagen.2013.11.023

Cited by 9 publications

(13 citation statements)

References 49 publications

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“…Reaction conditions were selected to prevent modification of the α,β-unsaturated carbonyl group shown to be essential for the activity of this class of compounds1920. The obtained drug-linked beads were incubated with protein extracts from Jurkat cells (human T lymphoblast-like cell line), selected for their susceptibility to 1 , as previously reported4. After incubation for 30 minutes, the beads were extensively washed to remove non-specific interacting proteins and the tight-bound ones were eluted and digested using trypsin as proteolytic agent.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that compound 1 affects the PI3K/AKT pathway and hence cell growth and proliferation while it induces apoptosis4. Based on the achieved results on the binding and transactivation potential of 1 towards PPARγ, we tested whether these effects were strictly dependent upon the binding to this receptor.…”

Section: Resultsmentioning

confidence: 99%

“…7b,c). We then assessed the effect of GW9662 on the levels of the phosphorylated form of AKT (p-AKT) to prove that 1 inhibits cell proliferation via the PI3K/AKT pathway4. Treatment with 1 alone caused a robust reduction of p-AKT, while pre-treatment with GW9662 resulted in its persistence, as shown by the western blot experiments of Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1). This is a semi-synthetic ent-kaurane diterpene with interesting anti-proliferative and pro-apoptotic activities towards different cancer cell lines3, obtained through the inhibition of the PI3K pathway and thus of AKT4. The direct target of action of this compound is, however, still undefined.…”

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confidence: 99%

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A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

Vasaturo

Fiengo

Tommasi

et al. 2017

Sci Rep

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Proteomics based approaches are emerging as useful tools to identify the targets of bioactive compounds and elucidate their molecular mechanisms of action. Here, we applied a chemical proteomic strategy to identify the peroxisome proliferator-activated receptor γ (PPARγ) as a molecular target of the pro-apoptotic agent 15-ketoatractyligenin methyl ester (compound 1). We demonstrated that compound 1 interacts with PPARγ, forms a covalent bond with the thiol group of C285 and occupies the sub-pocket between helix H3 and the β-sheet of the ligand-binding domain (LBD) of the receptor by Surface Plasmon Resonance (SPR), mass spectrometry-based studies and docking experiments. 1 displayed partial agonism of PPARγ in cell-based transactivation assays and was found to inhibit the AKT pathway, as well as its downstream targets. Consistently, a selective PPARγ antagonist (GW9662) greatly reduced the anti-proliferative and pro-apoptotic effects of 1, providing the molecular basis of its action. Collectively, we identified 1 as a novel PPARγ partial agonist and elucidated its mode of action, paving the way for therapeutic strategies aimed at tailoring novel PPARγ ligands with reduced undesired harmful side effects.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

Vasaturo

Fiengo

Tommasi

et al. 2017

Sci Rep

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“…Both gibberellins and ent -kauranes have noteworthy biological activity; the gibberellins as plant hormones and growth regulators 12–14 , and the ent -kauranes in a wide array of therapies. In fact, recent therapeutic applications of ent -kauranes include anti-inflammation 15 , anti-HIV 16 , antibacterial 17 , anti-tuberculosis 18 , and anti-cancer 19–23 . Clearly these molecular architectures have promising potential value.…”

Section: Introductionmentioning

confidence: 99%

The enantioselective construction of tetracyclic diterpene skeletons with Friedel–Crafts alkylation and palladium-catalyzed cycloalkenylation reactions

et al. 2015

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Due to the profound extent to which natural products inspire medicinal chemists in drug discovery, there is demand for innovative syntheses of these often complex materials. This article describes the synthesis of tricarbocyclic natural product architectures through an extension of the enantioselective Birch-Cope sequence with intramolecular Friedel-Crafts alkylation reactions. Additionally, palladium-catalyzed enol silane cycloalkenylation of the tricarbocyclic structures afforded the challenging bicyclo[3.2.1]octane C/D ring system found in the gibberellins and the ent-kauranes, two natural products with diverse medicinal value. In the case of the ent-kaurane derivative, an unprecedented alkene rearrangement converted four alkene isomers to one final product.

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Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

130

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Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

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Powerful tumor cell growth-inhibiting activity of a synthetic derivative of atractyligenin: Involvement of PI3K/Akt pathway and thioredoxin system

Cited by 9 publications

References 49 publications

A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

The enantioselective construction of tetracyclic diterpene skeletons with Friedel–Crafts alkylation and palladium-catalyzed cycloalkenylation reactions

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

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