3PO as a Selective Inhibitor of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 in A375 Human Melanoma Cells

Kotowski, Krzysztof; Supplitt, Stanisław; Wiczew, Daniel; Bartosik, Weronika; Saczko, Jolanta; Rossowska, Joanna; Drąg-Zalesińska, Małgorzata; Michel, Olga; Kulbacka, Julita

doi:10.21873/anticanres.14232

Cited by 17 publications

(11 citation statements)

References 49 publications

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“…Research on the effect of various inhibitors on melanoma has been widely documented. 3PO reported as a selective inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) has proapoptotic and anti-proliferative role in human melanoma cells A375 with BARF V600E mutation [40]. Juglone isolated from walnut trees synergizing BRAF inhibitor induced apoptosis in resistance melanoma cells A375R and SK-MEL-5R through ROS and p38-p53 pathway [41], while the effect of Lj-1-60 on resistance melanoma cells in our study needed to be further explored.…”

Section: Discussionmentioning

confidence: 99%

A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway

Tang

Long

et al. 2020

Cancer Cell Int

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Background: Fyn has been documented to have oncogenic features in multiple tumors, which might be a potential therapeutic target, however, few studies on the function role of Fyn and its specific inhibitors in melanoma. Methods: We investigated the impacts of Fyn and its inhibitor Lj-1-60 on melanoma through bioinformatics analysis, western blot, cell viability, cell cycle and apoptosis and xenograft tumor model as well as immunohistochemical staining. Pull-down and in vitro kinase assay were used to demonstrate Lj-1-60 targeting Fyn. Transcriptome sequencing and RT-PCR were adopted to confirm the potential mechanisms of Lj-1-60 in melanoma. Results: Our findings showed that Fyn was overexpressed in melanoma cells and knocked down of Fyn suppressed the proliferation of melanoma cells. To identify the potential inhibitors of Fyn, our in-house library including total of 111,277 chemicals was conducted to vitro screening, among those compounds, 83 inhibitors were further detected to explore the effect on melanoma cells growth and discovered a novel chalcone derivative Lj-1-60 that exhibited low cellular toxicity and high anti-tumor efficacy. Lj-1-60 directly was associated with Fyn and inhibited the Fyn kinase activity with Stat3 as substrate. What's more, Lj-1-60 suppressed the proliferation of melanoma in vitro and in vivo through inducing cell cycle arrest and apoptosis. Moreover, the activation of Stat3 had also been abrogated both in Lj-1-60 treated melanoma cells or Fyn knocked down cells. Conclusion: Our study revealed a novel Fyn inhibitor that could significantly suppress melanoma growth, which is a promising potential inhibitor for melanoma treatment.

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Section: Discussionmentioning

confidence: 99%

A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway

Tang

Long

et al. 2020

Cancer Cell Int

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“…In our main screening workflow ( Figure 2), we refined the high number of initial hits (1,122,542 compounds) to 14,240 compounds by selecting the best hits regarding shape overlap. The remaining compounds were docked into the active site of five representative structures of the protease using the experimentally validated [28] smina docking protocol. While the majority of compounds was scored with a value below −5.0 kcal/mol, 5490 potential hits were selected based on a score below the defined threshold of −7.0 kcal/mol.…”

Section: Virtual Screening Proceduresmentioning

confidence: 99%

“…In this study, we screened a large library of over 606 million compounds with the aim to discover novel inhibitors for the SARS-CoV-2 main protease. We designed a protocol consisting of a combination of intensively validated methods that were successfully applied in drug discovery programs either as standalone tools or in combination [25][26][27][28]. In a first step, we performed a shape-based screening with known binders for the SARS-CoV main protease and relevant substructures as template molecules.…”

Section: Introductionmentioning

confidence: 99%

Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds

Fischer

Sellner

Neranjan

et al. 2020

IJMS

142

102

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The rapid outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China followed by its spread around the world poses a serious global concern for public health. To this date, no specific drugs or vaccines are available to treat SARS-CoV-2 despite its close relation to the SARS-CoV virus that caused a similar epidemic in 2003. Thus, there remains an urgent need for the identification and development of specific antiviral therapeutics against SARS-CoV-2. To conquer viral infections, the inhibition of proteases essential for proteolytic processing of viral polyproteins is a conventional therapeutic strategy. In order to find novel inhibitors, we computationally screened a compound library of over 606 million compounds for binding at the recently solved crystal structure of the main protease (Mpro) of SARS-CoV-2. A screening of such a vast chemical space for SARS-CoV-2 Mpro inhibitors has not been reported before. After shape screening, two docking protocols were applied followed by the determination of molecular descriptors relevant for pharmacokinetics to narrow down the number of initial hits. Next, molecular dynamics simulations were conducted to validate the stability of docked binding modes and comprehensively quantify ligand binding energies. After evaluation of potential off-target binding, we report a list of 12 purchasable compounds, with binding affinity to the target protease that is predicted to be more favorable than that of the cocrystallized peptidomimetic compound. In order to quickly advise ongoing therapeutic intervention for patients, we evaluated approved antiviral drugs and other protease inhibitors to provide a list of nine compounds for drug repurposing. Furthermore, we identified the natural compounds (−)-taxifolin and rhamnetin as potential inhibitors of Mpro. Rhamnetin is already commercially available in pharmacies.

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“…The cytotoxicity of vanicosides against two normal cell lines—keratinocytes (HaCaT) and the primary fibroblast line—was also tested. According to previous data, the hyperactivation of the ERK pathway by the BRAFV600E mutation in A375 cells is the main factor of its tumorigenesis [ 18 ]. The C32 cell line is also a BRAFV600E mutant [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Effect of Vanicosides A and B from Reynoutria sachalinensis against Melanotic and Amelanotic Melanoma Cell Lines and in silico Evaluation for Inhibition of BRAFV600E and MEK1

Nawrot-Hadzik

Choromańska

Abel

et al. 2020

IJMS

Self Cite

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Vanicosides A and B are the esters of hydroxycinnamic acids with sucrose, occurring in a few plant species from the Polygonaceae family. So far, vanicosides A and B have not been evaluated for anticancer activity against human malignant melanoma. In this study, we tested these two natural products, isolated from Reynoutria sachalinensis rhizomes, against two human melanoma cell lines (amelanotic C32 cell line and melanotic A375 cell line, both bearing endogenous BRAFV600E mutation) and two normal human cell lines—keratinocytes (HaCaT) and the primary fibroblast line. Additionally, a molecular docking of vanicoside A and vanicoside B with selected targets involved in melanoma progression was performed. Cell viability was studied using an MTT assay. A RealTime-Glo™ Annexin V Apoptosis and Necrosis assay was used for monitoring programmed cell death (PCD). Vanicoside A demonstrated strong cytotoxicity against the amelanotic C32 cell line (viability of the C32 cell line was decreased to 55% after 72 h incubation with 5.0 µM of vanicoside A), significantly stronger than vanicoside B. This stronger cytotoxic activity can be attributed to an additional acetyl group in vanicoside A. No significant differences in the cytotoxicity of vanicosides were observed against the less sensitive A375 cell line. Moreover, vanicosides caused the death of melanoma cells at concentrations from 2.5 to 50 µM, without harming the primary fibroblast line. The keratinocyte cell line (HaCaT) was more sensitive to vanicosides than fibroblasts, showing a clear decrease in viability after incubation with 25 µM of vanicoside A as well as a significant phosphatidylserine (PS) exposure, but without a measurable cell death-associated fluorescence. Vanicosides induced an apoptotic death pathway in melanoma cell lines, but because of the initial loss of cell membrane integrity, an additional cell death mechanism might be involved like permeability transition pore (PTP)-mediated necrosis that needs to be explored in the future. Molecular docking indicated that both compounds bind to the active site of the BRAFV600E kinase and MEK-1 kinase; further experiments on their specific inhibitory activity of these targets should be considered.

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3PO as a Selective Inhibitor of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 in A375 Human Melanoma Cells

Cited by 17 publications

References 49 publications

A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway

A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway

Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds

Cytotoxic Effect of Vanicosides A and B from Reynoutria sachalinensis against Melanotic and Amelanotic Melanoma Cell Lines and in silico Evaluation for Inhibition of BRAFV600E and MEK1

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