Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death

Ligia I. Bastea, Laeticia M.A. Hollant, Heike R. Döppler, Elizabeth M. Reid, Peter Storz

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number16588
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

sangivamycin
Pancreatic Neoplasms
Histones
Cell Death
gemcitabine
Toyocamycin
Cell Line
Neoplasms
Tumor Microenvironment
Immunosuppressive Agents
Nucleosides
Mitosis
Phosphotransferases
Therapeutics
Survival Rate
Phosphorylation
Cell Proliferation
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death. / Bastea, Ligia I.; Hollant, Laeticia M.A.; Döppler, Heike R.; Reid, Elizabeth M.; Storz, Peter.

In: Scientific reports, Vol. 9, No. 1, 16588, 01.12.2019.

Research output: Contribution to journalArticle

Bastea, Ligia I. ; Hollant, Laeticia M.A. ; Döppler, Heike R. ; Reid, Elizabeth M. ; Storz, Peter. / Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death. In: Scientific reports. 2019 ; Vol. 9, No. 1.
@article{96b0a0d42d7e4d64abd1ad3657049db1,
title = "Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death",
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.",
author = "Bastea, {Ligia I.} and Hollant, {Laeticia M.A.} and D{\"o}ppler, {Heike R.} and Reid, {Elizabeth M.} and Peter Storz",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-53223-0",
language = "English (US)",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death

AU - Bastea, Ligia I.

AU - Hollant, Laeticia M.A.

AU - Döppler, Heike R.

AU - Reid, Elizabeth M.

AU - Storz, Peter

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85075071092&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075071092&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-53223-0

DO - 10.1038/s41598-019-53223-0

M3 - Article

C2 - 31719634

AN - SCOPUS:85075071092

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 16588

ER -