Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death.
Sci Rep
; 9(1): 16588, 2019 11 12.
Article
em En
| MEDLINE
| ID: mdl-31719634
ABSTRACT
Current treatment options for patients with pancreatic cancer are suboptimal, resulting in a five year survival rate of about 9%. Difficulties with treatment are due to an immunosuppressive, fibrotic tumor microenvironment that prevents drugs from reaching tumor cells, but also to the limited efficacy of existing FDA-approved chemotherapeutic compounds. We here show that the nucleoside analog Sangivamycin and its closely-related compound Toyocamycin target PDA cell lines, and are significantly more efficient than Gemcitabine. Using KINOMEscan screening, we identified the kinase Haspin, which is overexpressed in PDA cell lines and human PDA samples, as a main target for both compounds. Inhibition of Haspin leads to a decrease in Histone H3 phosphorylation and prevents Histone H3 binding to survivin, thus providing mechanistic insight of how Sangivamycin targets cell proliferation, mitosis and induces apoptotic cell death. In orthotopically implanted tumors in mice, Sangivamycin was efficient in decreasing the growth of established tumors. In summary, we show that Sangivamycin and derivatives can be an efficient new option for treatment of PDA.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Nucleosídeos de Pirimidina
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Histonas
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Regulação Neoplásica da Expressão Gênica
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Proteínas Serina-Treonina Quinases
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Apoptose
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Peptídeos e Proteínas de Sinalização Intracelular
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Survivina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article