HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice

Thaiz Ferraz Borin, Debora A.P.C. Zuccari, Bruna V. Jardim-Perassi, Lívia C. Ferreira, A. S.M. Iskander, Nadimpalli Ravi S. Varma, Adarsh Shankar, Austin M. Guo, Guillermo Scicli, Ali Syed Arbab

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Abstract

A selective inhibitor of 20-HETE synthesis, HET0016, has been reported to inhibit angiogenesis. 20-HETE has been known as a second mitogenic messenger of angiogenesis inducing growth factors. HET0016 effects were analyzed on MDA-MB-231 derived breast cancer in mouse and in vitro cell line. MDA-MB-231 tumor cells were implanted in animals' right flank and randomly assigned to early (1 and 2), starting treatments on day 0, or delayed groups (3 and 4) on day 8 after implantation of tumor. Animals received HET0016 (10 mg/kg) treatment via intraperitoneal injection for 5 days/week for either 3 or 4 weeks. Control group received vehicle treatment. Tumor sizes were measured on days 7, 14, 21, and 28 and the animals were euthanized on day 22 and 29. Proteins were extracted from the whole tumor and from cells treated with 10 μM HET0016 for 4 and 24 hrs. Protein array kits of 20 different cytokines/factors were used. ELISA was performed to observe the HIF-1α and MMP-2 protein expression. Other markers were confirmed by IHC. HET0016 significantly inhibited tumor growth in all treatment groups at all-time points compared to control (p<0.05). Tumor growth was completely inhibited on three of ten animals on early treatment group. Treatment groups showed significantly lower expression of pro-angiogenic factors compared to control at 21 days; however, there was no significant difference in HIF-1α expression after treatments. Similar results were found in vitro at 24 hrs of HET0016 treatment. After 28 days, significant increase of angiogenin, angiopoietin-1/2, EGF-R and IGF-1 pro-angiogenic factors were found (p<0.05) compared to control, as well as an higher intensity of all factors were found when compared to that of 21 day's data, suggesting a treatment resistance. HET0016 inhibited tumor growth by reducing expression of different set of pro-angiogenic factors; however, a resistance to treatment seemed to happen after 21 days.

Original languageEnglish (US)
Article numbere116247
JournalPloS one
Volume9
Issue number12
DOIs
StatePublished - Dec 30 2014

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Triple Negative Breast Neoplasms
Angiogenesis Inducing Agents
breast neoplasms
Tumors
neoplasms
synthesis
mice
Growth
Animals
angiogenesis
Neoplasms
Therapeutics
Cells
animals
gelatinase A
Angiopoietin-1
second messengers
Proteins
intraperitoneal injection
animal welfare

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice. / Borin, Thaiz Ferraz; Zuccari, Debora A.P.C.; Jardim-Perassi, Bruna V.; Ferreira, Lívia C.; Iskander, A. S.M.; Varma, Nadimpalli Ravi S.; Shankar, Adarsh; Guo, Austin M.; Scicli, Guillermo; Arbab, Ali Syed.

In: PloS one, Vol. 9, No. 12, e116247, 30.12.2014.

Research output: Contribution to journalArticle

Borin, TF, Zuccari, DAPC, Jardim-Perassi, BV, Ferreira, LC, Iskander, ASM, Varma, NRS, Shankar, A, Guo, AM, Scicli, G & Arbab, AS 2014, 'HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice', PloS one, vol. 9, no. 12, e116247. https://doi.org/10.1371/journal.pone.0116247
Borin, Thaiz Ferraz ; Zuccari, Debora A.P.C. ; Jardim-Perassi, Bruna V. ; Ferreira, Lívia C. ; Iskander, A. S.M. ; Varma, Nadimpalli Ravi S. ; Shankar, Adarsh ; Guo, Austin M. ; Scicli, Guillermo ; Arbab, Ali Syed. / HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice. In: PloS one. 2014 ; Vol. 9, No. 12.
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abstract = "A selective inhibitor of 20-HETE synthesis, HET0016, has been reported to inhibit angiogenesis. 20-HETE has been known as a second mitogenic messenger of angiogenesis inducing growth factors. HET0016 effects were analyzed on MDA-MB-231 derived breast cancer in mouse and in vitro cell line. MDA-MB-231 tumor cells were implanted in animals' right flank and randomly assigned to early (1 and 2), starting treatments on day 0, or delayed groups (3 and 4) on day 8 after implantation of tumor. Animals received HET0016 (10 mg/kg) treatment via intraperitoneal injection for 5 days/week for either 3 or 4 weeks. Control group received vehicle treatment. Tumor sizes were measured on days 7, 14, 21, and 28 and the animals were euthanized on day 22 and 29. Proteins were extracted from the whole tumor and from cells treated with 10 μM HET0016 for 4 and 24 hrs. Protein array kits of 20 different cytokines/factors were used. ELISA was performed to observe the HIF-1α and MMP-2 protein expression. Other markers were confirmed by IHC. HET0016 significantly inhibited tumor growth in all treatment groups at all-time points compared to control (p<0.05). Tumor growth was completely inhibited on three of ten animals on early treatment group. Treatment groups showed significantly lower expression of pro-angiogenic factors compared to control at 21 days; however, there was no significant difference in HIF-1α expression after treatments. Similar results were found in vitro at 24 hrs of HET0016 treatment. After 28 days, significant increase of angiogenin, angiopoietin-1/2, EGF-R and IGF-1 pro-angiogenic factors were found (p<0.05) compared to control, as well as an higher intensity of all factors were found when compared to that of 21 day's data, suggesting a treatment resistance. HET0016 inhibited tumor growth by reducing expression of different set of pro-angiogenic factors; however, a resistance to treatment seemed to happen after 21 days.",
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AU - Jardim-Perassi, Bruna V.

AU - Ferreira, Lívia C.

AU - Iskander, A. S.M.

AU - Varma, Nadimpalli Ravi S.

AU - Shankar, Adarsh

AU - Guo, Austin M.

AU - Scicli, Guillermo

AU - Arbab, Ali Syed

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