SK119, a Novel Shikonin Derivative, Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib
Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range an...
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/10/5684 |
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| author | Nadine Kretschmer Christin Durchschein Antje Hufner Beate Rinner Birgit Lohberger Rudolf Bauer |
| author_facet | Nadine Kretschmer Christin Durchschein Antje Hufner Beate Rinner Birgit Lohberger Rudolf Bauer |
| author_sort | Nadine Kretschmer |
| collection | DOAJ |
| description | Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC<sub>50</sub> values in a nano-molar range, induced apoptosis and led to a dose-dependent increase in the expression and protein phosphorylation of HSP27 and HSP90 in WM9 and MUG-Mel 2 cells. Combinatorial treatment, which is highly recommended in melanoma, revealed the synergistic effects of SK119 with vemurafenib and cobimetinib. SK119 treatment changed the expression levels of apoptosis genes and death receptor expression and exhibited synergistic effects with vemurafenib and cobimetinib in human melanoma cells. Further research indicates a promising potential in melanoma therapy. |
| first_indexed | 2024-03-10T03:43:58Z |
| format | Article |
| id | doaj.art-e66f54b2f0a24c18bc44bddc5e9996fe |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:43:58Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e66f54b2f0a24c18bc44bddc5e9996fe2023-11-23T11:26:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012310568410.3390/ijms23105684SK119, a Novel Shikonin Derivative, Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and CobimetinibNadine Kretschmer0Christin Durchschein1Antje Hufner2Beate Rinner3Birgit Lohberger4Rudolf Bauer5Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Beethovenstr. 8, 8010 Graz, AustriaInstitute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Beethovenstr. 8, 8010 Graz, AustriaInstitute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Universitaetsplatz 1, 8010 Graz, AustriaDivision of Biomedical Research, Medical University Graz, Roseggerweg 48, 8036 Graz, AustriaDepartment of Orthopedics and Trauma, Medical University Graz, Auenbruggerplatz 5, 8036 Graz, AustriaInstitute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Beethovenstr. 8, 8010 Graz, AustriaMelanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC<sub>50</sub> values in a nano-molar range, induced apoptosis and led to a dose-dependent increase in the expression and protein phosphorylation of HSP27 and HSP90 in WM9 and MUG-Mel 2 cells. Combinatorial treatment, which is highly recommended in melanoma, revealed the synergistic effects of SK119 with vemurafenib and cobimetinib. SK119 treatment changed the expression levels of apoptosis genes and death receptor expression and exhibited synergistic effects with vemurafenib and cobimetinib in human melanoma cells. Further research indicates a promising potential in melanoma therapy.https://www.mdpi.com/1422-0067/23/10/5684shikonin dimershikoninmelanomaapoptosissynergismvemurafenib |
| spellingShingle | Nadine Kretschmer Christin Durchschein Antje Hufner Beate Rinner Birgit Lohberger Rudolf Bauer SK119, a Novel Shikonin Derivative, Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib International Journal of Molecular Sciences shikonin dimer shikonin melanoma apoptosis synergism vemurafenib |
| title | SK119, a Novel Shikonin Derivative, Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib |
| title_full | SK119, a Novel Shikonin Derivative, Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib |
| title_fullStr | SK119, a Novel Shikonin Derivative, Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib |
| title_full_unstemmed | SK119, a Novel Shikonin Derivative, Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib |
| title_short | SK119, a Novel Shikonin Derivative, Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib |
| title_sort | sk119 a novel shikonin derivative leads to apoptosis in melanoma cell lines and exhibits synergistic effects with vemurafenib and cobimetinib |
| topic | shikonin dimer shikonin melanoma apoptosis synergism vemurafenib |
| url | https://www.mdpi.com/1422-0067/23/10/5684 |
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