The tetrahydroxanthone-dimer phomoxanthone A is a strong inducer of apoptosis in cisplatin-resistant solid cancer cells

Wang, Chenyin; Engelke, Laura; Bickel, David; Hamacher, Alexandra; Frank, Mary Margaret; Proksch, Peter; Gohlke, Holger; Kassack, Matthias U.

doi:10.1016/j.bmc.2019.115044

Cited by 15 publications

(18 citation statements)

References 41 publications

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“…PXA was also reported to be a mitochondrial toxin. 12 These results implied that PXA and PXB may be multitarget compounds to inhibit the growth of tumor cells. Further investigations are required to evaluate the antitumor mechanisms of PXA and PXB.…”

Section: Resultsmentioning

confidence: 93%

Identification of Phomoxanthone A and B as Protein Tyrosine Phosphatase Inhibitors

Gao

Zhao

et al. 2020

ACS Omega

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Phomoxanthone A and B (PXA and PXB) are xanthone dimers and isolated from the endophytic fungus Phomopsis sp. By254. The results demonstrated that PXB and PXA are noncompetitive inhibitors of SHP2 and PTP1B and competitive inhibitors of SHP1. Molecular docking studies showed that PXB and PXA interact with conserved domains of protein tyrosine phosphatases such as the β5-β6 loop, WPD loop, P loop, and Q loop. PXA and PXB could significantly inhibit the cell proliferation in MCF7 cells. Our results indicated that these two compounds do not efficiently inhibit PTP1B and SHP2 activity. RNA sequencing showed that PXA and PXB may inhibit SHP1 activity in MCF7 cells leading to the upregulation of inflammatory factors. In addition to PTP inhibition, PXA and PXB are multitarget compounds to inhibit the proliferation of tumor cells. In conclusion, both compounds show inhibition of cancer cells and a certain degree of inflammatory stimulation, which make them promising for tumor immunotherapy.

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Section: Resultsmentioning

confidence: 93%

Identification of Phomoxanthone A and B as Protein Tyrosine Phosphatase Inhibitors

Gao

Zhao

et al. 2020

ACS Omega

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“…It is interesting that PXA was first identified as an antimalarial compound, revealing its strong antibiotic activity against the protozoan parasite Plasmodium falciparum, then against Mycobacterium tuberculosis and against two human cancer cells lines [1] Furthermore, its reported antibiotic activity has been investigated against the alga Chlorella fusca, the fungus Ustilago violacea, and the bacterium Bacillus megaterium. This broad range of activity against bacteria, protozoans, fungi, plants, and animal cells banned it as a specific antibiotic, promoting, on the other side, its anti-cancer profile, since it was more toxic against human cancer cells than non-cancer cells [2][3][4][5]. More recently, it has been enlightened that PXA might have an application as a tool in the study of mitochondrial membrane dynamics, particularly non-canonical mitochondrial fission and remodeling of the mitochondrial matrix.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, it has been enlightened that PXA might have an application as a tool in the study of mitochondrial membrane dynamics, particularly non-canonical mitochondrial fission and remodeling of the mitochondrial matrix. Indeed, PXA mainly causes cristae disruption and fragmentation of the matrix [3][4][5]. Intrigued by its spread biological profile, our MS-based proteomics research moved to the target(s) discovery of this natural compound through a combined strategy consisting of MS-based DARTS and t-LiP-MRM.…”

Section: Discussionmentioning

confidence: 99%

“…This dual effect could help in counteracting resistance phenomena during chemotherapy [ 2 , 3 ]. More recently, PXA also displayed robust cytotoxicity against different solid tumor cells and their cisplatin-resistant sub-cells, with IC 50 values in the high nanomolar/low micromolar range, as in ovarian cancer and bladder cancer cell pairs [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Carbamoyl-Phosphate Synthase 1 as a Novel Target of Phomoxanthone A, a Bioactive Fungal Metabolite

et al. 2020

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Phomoxanthone A, a bioactive xanthone dimer isolated from the endophytic fungus Phomopsis sp., is a mitochondrial toxin weakening cellular respiration and electron transport chain activity by a fast breakup of the mitochondrial assembly. Here, a multi-disciplinary strategy has been developed and applied for identifying phomoxanthone A target(s) to fully address its mechanism of action, based on drug affinity response target stability and targeted limited proteolysis. Both approaches point to the identification of carbamoyl-phosphate synthase 1 as a major phomoxanthone A target in mitochondria cell lysates, giving also detailed insights into the ligand/target interaction sites by molecular docking and assessing an interesting phomoxanthone A stimulating activity on carbamoyl-phosphate synthase 1. Thus, phomoxanthone A can be regarded as an inspiring molecule for the development of new leads in counteracting hyperammonemia states.

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“…The apoptosis assay was performed as previously described [42]. Briefly, cells were seeded in 24-well plates and incubated overnight.…”

Section: Apoptosis Assaymentioning

confidence: 99%

Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1

Wang

Hamacher

Petzsch

et al. 2020

Cancers

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Occurrence of cisplatin-resistance in bladder cancer is frequent and results in disease progression. Thus, novel therapeutic approaches are a high medical need for patients suffering from chemotherapy failure. The purpose of this study was to test the combination of the DNA methyltransferase inhibitor decitabine (DAC) with the histone deacetylase inhibitor entinostat (ENT) in bladder cancer cells with different platinum sensitivities: J82, cisplatin-resistant J82CisR, and RT-112. Intermittent treatment of J82 cells with cisplatin resulted in the six-fold more cisplatin-resistant cell line J82CisR. Combinations of DAC and/or ENT plus cisplatin could not reverse chemoresistance. However, the combination of DAC and ENT acted cytotoxic in a highly synergistic manner as shown by Chou-Talalay analysis via induction of apoptosis and cell cycle arrest. Importantly, this effect was cancer cell-selective as no synergism was found for the combination in the non-cancerous urothelial cell line HBLAK. Expression analysis indicated that epigenetic treatment led to up-regulation of forkhead box class O1 (FoxO1) and further activated proapoptotic Bim and the cell cycle regulator p21 and reduced expression of survivin in J82CisR. In conclusion, the combination of DAC and ENT is highly synergistic and has a promising potential for therapy of bladder cancer, particularly in cases with platinum resistance.

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The tetrahydroxanthone-dimer phomoxanthone A is a strong inducer of apoptosis in cisplatin-resistant solid cancer cells

Cited by 15 publications

References 41 publications

Identification of Phomoxanthone A and B as Protein Tyrosine Phosphatase Inhibitors

Identification of Phomoxanthone A and B as Protein Tyrosine Phosphatase Inhibitors

Carbamoyl-Phosphate Synthase 1 as a Novel Target of Phomoxanthone A, a Bioactive Fungal Metabolite

Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1

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