Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Florio, Rosalba; Lellis, Laura De; Veschi, Serena; Verginelli, Fabio; Giacomo, Viviana di; Gallorini, M.; Perconti, Silvia; Sanna, Mario; Natale, Angelica; Arduini, Arduino; Amoroso, Rosa; Cataldi, Amelia; Cama, Alessandro

doi:10.1038/s41598-018-31797-5

Cited by 31 publications

(33 citation statements)

References 45 publications

(51 reference statements)

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“…Cell viability was assessed by MTT assay, as previously described [55]. Briefly, cells were seeded in 96-well plates (4 × 10 3 cells/well) and incubated for 24 h. For initial screening, cells were exposed for 72 h to fenbendazole, mebendazole, oxibendazole or parbendazole at different concentrations as indicated, or to vehicle (DMSO).…”

Section: Cell Viability and Cell Growth Assaysmentioning

confidence: 99%

“…Then, cells were suspended in 5 µg/mL PI (final concentration) and 100 µg/mL RNAse (final concentration), and incubated at 4 • C overnight. Cell cycle profiles were analyzed as previously described [55].…”

Section: Cell Cycle Analysismentioning

confidence: 99%

“…Apoptosis assay was performed essentially as previously described [55]. Analyses were performed using a CytoFLEX flow cytometer with the FL1 detector (linear mode) and the CytoExpert software (Beckmann Coulter, Milano, Italy).…”

Section: Apoptosis Assaymentioning

confidence: 99%

“…PC cell lines treated with 0.2 µM, 0.7 µM parbendazole, or with vehicle (DMSO) were lysed in a cell lysis buffer containing PMSF, protease inhibitors cocktails and phosphatase inhibitors. Protein lysate quantification and immunoblot analyses were performed as previously described [55].…”

Section: Western Blotting Analysismentioning

confidence: 99%

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The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

Florio

Veschi

Giacomo

et al. 2019

Cancers

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Pancreatic cancer (PC) is one of the most lethal, chemoresistant malignancies and it is of paramount importance to find more effective therapeutic agents. Repurposing of non-anticancer drugs may expand the repertoire of effective molecules. Studies on repurposing of benzimidazole-based anthelmintics in PC and on their interaction with agents approved for PC therapy are lacking. We analyzed the effects of four Food and Drug Administration (FDA)-approved benzimidazoles on AsPC-1 and Capan-2 pancreatic cancer cell line viability. Notably, parbendazole was the most potent benzimidazole affecting PC cell viability, with half maximal inhibitory concentration (IC50) values in the nanomolar range. The drug markedly inhibited proliferation, clonogenicity and migration of PC cell lines through mechanisms involving alteration of microtubule organization and formation of irregular mitotic spindles. Moreover, parbendazole interfered with cell cycle progression promoting G2/M arrest, followed by the emergence of enlarged, polyploid cells. These abnormalities, suggesting a mitotic catastrophe, culminated in PC cell apoptosis, are also associated with DNA damage in PC cell lines. Remarkably, combinations of parbendazole with gemcitabine, a drug employed as first-line treatment in PC, synergistically decreased PC cell viability. In conclusion, this is the first study providing evidence that parbendazole as a single agent, or in combination with gemcitabine, is a repurposing candidate in the currently dismal PC therapy.

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Section: Cell Viability and Cell Growth Assaysmentioning

confidence: 99%

Section: Cell Cycle Analysismentioning

confidence: 99%

Section: Apoptosis Assaymentioning

confidence: 99%

Section: Western Blotting Analysismentioning

confidence: 99%

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The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

Florio

Veschi

Giacomo

et al. 2019

Cancers

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“…Although the preliminary study of DCA shows the slowdown growth of certain tumors, the mechanism is not well developed. Several antitumor agents show improved efficacy when taken in combination with DCA (Florio et al, ). As far as we are aware, only one article reported the dichloroacetic acid derivatives for antibacterial properties (Casini, Ferappi, & Grifantini, ).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, antimicrobial, and DNA gyrase inhibitory properties of fluoroquinolone–dichloroacetic acid hybrids

et al. 2019

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A series of new fluoroquinolone conjugates 8a-g and 9a-f were synthesized via benzotriazole-mediated synthetic approach with good yield and purity. Some of the synthesized analogs exhibited significant antibacterial properties against Escherichia coli and Staphylococcus aureus with potency higher than that of the parent drugs through in vitro standard bioassay procedure (conjugates 8c and 8d reveal antimicrobial properties with potency 1.9, 61.9, 20.7 and 2.4, 37.1, 8.3 folds relative to the parent antibiotic 6 against E. coli, S. aureus, and Enterococcus faecalis, respectively). The observed experimental data were supported by enzymatic DNA gyrase inhibitory property. Developed BMLR-QSAR model validates the observed experimental data and recognizes the parameters responsible for the enhanced antibacterial properties. K E Y W O R D S antibacterial, dichloroacetic acid, DNA gyrase, fluoroquinolone, hybrid conjugates F I G U R E 1 Examples of different class of antibiotics 250 | SELIEM Et aL.to microwave irradiation (Discover mode; run time: 60 s; Power Max-cooling mode). N-(Boc-aminoacyl)benzotriazoles 10a-g (Panda, Hall, et al., 2014; Panda, Naumov, et al., 2014) Compounds 10a-g were synthesized by irradiating an equimolar amount of Boc-protected amino acid with 1-(methylsulfonyl)-1H-benzo[d] [1,2,3]triazole (BtSO 2 Me) in the presence of 2.0 eq. of triethylamine for 2 min run time and 60 min hold time at 70°C and 50 W irradiation power. Completion of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with water. The product obtained was extracted with ethyl acetate and then washed with a saturated solution of sodium carbonate and water to afford compound 10a-g. | General procedure for the preparation of

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FGF23 regulates atrial fibrosis in atrial fibrillation by mediating the STAT3 and SMAD3 pathways

Dong

Wang³

et al. 2019

Journal Cellular Physiology

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High fibroblast growth factor 23 (FGF23) concentrations are a strong predictor of atrial fibrillation (AF), but researchers have not clearly determined the mechanism by which FGF23 causes atrial fibrosis in patients with AF. This study aims to elucidate the mechanism by which FGF23 induces atrial fibrosis in patients with AF.Immunohistochemistry was used to study the expression of FGF23, FGFR4, and fibrotic factors in patients with a normal sinus rhythm (SR) and patients with AF. Cardiac fibroblasts (CFs) were cocultured with different concentrations of the recombinant FGF23 protein. Compared with the SR group, the levels of FGF23, FGFR4, α-smooth muscle actin (α-SMA), and collagen-1 were significantly increased in the AF group. Exposure to high concentrations of the recombinant FGF23 protein increased the accumulation of reactive oxygen species (ROS) and activated α-SMA, collagen-1, signal transducer and activator of transcription 3 (STAT3) and SMAD3 signaling in cultured CFs. The levels of fibrotic proteins in CFs stimulated with high concentrations of the recombinant FGF23 protein were reversed by N-acetylcysteine (NAC, a ROS inhibitor), ship information system 3 (a SMAD3 inhibitor), and Stattic (a STAT3 inhibitor). Furthermore, compared to untreated CFs, CFs treated with the recombinant FGF23 protein were characterized by an increased interaction between STAT3 and SMAD3. Based on these results, FGF23 induces atrial fibrosis in patients with AF by increasing ROS production and subsequently activating STAT3 and SMAD3 signaling. K E Y W O R D S atrial fibrillation, atrial fibrosis, FGF23, ROS, STAT3

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Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Cited by 31 publications

References 45 publications

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

Design, synthesis, antimicrobial, and DNA gyrase inhibitory properties of fluoroquinolone–dichloroacetic acid hybrids

FGF23 regulates atrial fibrosis in atrial fibrillation by mediating the STAT3 and SMAD3 pathways

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