A Thia-Analogous Indirubin <i>N</i>-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells
Skin cancer is the most common malignant disease worldwide and, therefore, also poses a challenge from a pharmacotherapeutic perspective. Derivatives of indirubin are an interesting option in this context. In the present study, the effects of 3-[3′-oxo-benzo[<i>b</i>]thiophen-2′-(<i&g...
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MDPI AG
2023-10-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/19/2409 |
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| author | Franziska Wendt Felix Wittig Anne Rupprecht Robert Ramer Peter Langer Steffen Emmert Marcus Frank Burkhard Hinz |
| author_facet | Franziska Wendt Felix Wittig Anne Rupprecht Robert Ramer Peter Langer Steffen Emmert Marcus Frank Burkhard Hinz |
| author_sort | Franziska Wendt |
| collection | DOAJ |
| description | Skin cancer is the most common malignant disease worldwide and, therefore, also poses a challenge from a pharmacotherapeutic perspective. Derivatives of indirubin are an interesting option in this context. In the present study, the effects of 3-[3′-oxo-benzo[<i>b</i>]thiophen-2′-(<i>Z</i>)-ylidene]-1-(β-<span style="font-variant: small-caps;">d</span>-glucopyranosyl)-oxindole (KD87), a thia-analogous indirubin <i>N</i>-glycoside, on the viability and mitochondrial properties of melanoma (A375) and squamous cell carcinoma cells (A431) of the skin were investigated. In both cell lines, KD87 caused decreased viability, the activation of caspases-3 and -7, and the inhibition of colony formation. At the mitochondrial level, a concentration-dependent decrease in both the basal and ATP-linked oxygen consumption rate and in the reserve capacity of oxidative respiration were registered in the presence of KD87. These changes were accompanied by morphological alterations in the mitochondria, a release of mitochondrial cytochrome c into the cytosol and significant reductions in succinate dehydrogenase complex subunit B (SDHB, subunit of complex II) in A375 and A431 cells and NADH:ubiquinone oxidoreductase subunit B8 (NDUFB8, subunit of complex I) in A375 cells. The effect of KD87 was accompanied by a significant upregulation of the enzyme heme oxygenase-1, whose inhibition led to a partial but significant reduction in the metabolic-activity-reducing effect of KD87. In summary, our data show a mitochondria-targeting effect of KD87 as part of the cytotoxic effect of this compound on skin cancer cells, which should be considered in future studies with this class of compounds. |
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| language | English |
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| publishDate | 2023-10-01 |
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| spelling | doaj.art-e4d653d7f8ce482784066c1f5d33ff3b2023-11-19T14:13:25ZengMDPI AGCells2073-44092023-10-011219240910.3390/cells12192409A Thia-Analogous Indirubin <i>N</i>-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma CellsFranziska Wendt0Felix Wittig1Anne Rupprecht2Robert Ramer3Peter Langer4Steffen Emmert5Marcus Frank6Burkhard Hinz7Institute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, GermanyInstitute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, GermanyInstitute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, GermanyInstitute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, GermanyInstitute of Organic Chemistry, University of Rostock, 18059 Rostock, GermanyClinic and Policlinic for Dermatology, Rostock University Medical Centre, 18057 Rostock, GermanyElectron Microscopy Centre, Rostock University Medical Centre, 18057 Rostock, GermanyInstitute of Pharmacology and Toxicology, Rostock University Medical Centre, 18057 Rostock, GermanySkin cancer is the most common malignant disease worldwide and, therefore, also poses a challenge from a pharmacotherapeutic perspective. Derivatives of indirubin are an interesting option in this context. In the present study, the effects of 3-[3′-oxo-benzo[<i>b</i>]thiophen-2′-(<i>Z</i>)-ylidene]-1-(β-<span style="font-variant: small-caps;">d</span>-glucopyranosyl)-oxindole (KD87), a thia-analogous indirubin <i>N</i>-glycoside, on the viability and mitochondrial properties of melanoma (A375) and squamous cell carcinoma cells (A431) of the skin were investigated. In both cell lines, KD87 caused decreased viability, the activation of caspases-3 and -7, and the inhibition of colony formation. At the mitochondrial level, a concentration-dependent decrease in both the basal and ATP-linked oxygen consumption rate and in the reserve capacity of oxidative respiration were registered in the presence of KD87. These changes were accompanied by morphological alterations in the mitochondria, a release of mitochondrial cytochrome c into the cytosol and significant reductions in succinate dehydrogenase complex subunit B (SDHB, subunit of complex II) in A375 and A431 cells and NADH:ubiquinone oxidoreductase subunit B8 (NDUFB8, subunit of complex I) in A375 cells. The effect of KD87 was accompanied by a significant upregulation of the enzyme heme oxygenase-1, whose inhibition led to a partial but significant reduction in the metabolic-activity-reducing effect of KD87. In summary, our data show a mitochondria-targeting effect of KD87 as part of the cytotoxic effect of this compound on skin cancer cells, which should be considered in future studies with this class of compounds.https://www.mdpi.com/2073-4409/12/19/2409thia-analogous indirubin <i>N</i>-glycosideskin cancermelanoma cellssquamous cell carcinoma cellsheme oxygenase-1mitochondria |
| spellingShingle | Franziska Wendt Felix Wittig Anne Rupprecht Robert Ramer Peter Langer Steffen Emmert Marcus Frank Burkhard Hinz A Thia-Analogous Indirubin <i>N</i>-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells Cells thia-analogous indirubin <i>N</i>-glycoside skin cancer melanoma cells squamous cell carcinoma cells heme oxygenase-1 mitochondria |
| title | A Thia-Analogous Indirubin <i>N</i>-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells |
| title_full | A Thia-Analogous Indirubin <i>N</i>-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells |
| title_fullStr | A Thia-Analogous Indirubin <i>N</i>-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells |
| title_full_unstemmed | A Thia-Analogous Indirubin <i>N</i>-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells |
| title_short | A Thia-Analogous Indirubin <i>N</i>-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells |
| title_sort | thia analogous indirubin i n i glycoside disrupts mitochondrial function and causes the death of human melanoma and cutaneous squamous cell carcinoma cells |
| topic | thia-analogous indirubin <i>N</i>-glycoside skin cancer melanoma cells squamous cell carcinoma cells heme oxygenase-1 mitochondria |
| url | https://www.mdpi.com/2073-4409/12/19/2409 |
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