In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells

Tuba Ozbay, Donald L Durden, Tongrui Liu, Ruth M. O'Regan, Rita Nahta

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Purpose: The purpose of the current study is to determine the in vitro cytotoxic effects of the novel pan-PI3-kinase inhibitor SF1126 in HER2-over-expressing breast cancer cells. Methods: Cell proliferation and cytotoxicity were examined by MTS colorimetric assay, FACS analysis, colony formation assay, and immunoblotting. Phosphoinositol-3-kinase signaling was assessed by immunoblotting for phosphorylated Akt. Combination effects of trastuzumab and SF1126 were examined in resistant cells by MTS and soft agar assay. Results: SF1126 inhibited proliferation, and induced G1 arrest and apoptosis of SKBR3 and BT474 parental and trastuzumab-resistant HER2-over-expressing cells. Colony formation was inhibited by SF1126, caspase 3 and PARP proteins were cleaved, and survivin was down-regulated. Inhibition of PI3-kinase was confirmed by reduced phosphorylation of Akt. Finally, the combination of SF1126 and trastuzumab synergistically inhibited proliferation of resistant cells, with SF1126-treated cells showing reduced anchorage- independent growth. Conclusions: These results provide evidence that a clinically relevant pan-PI-3 kinase inhibitor can reverse trastuzumab resistance in breast cancer cells, and support further study of PI3-kinase inhibitor SF1126 in HER2-over-expressing breast cancer cells, including those that have progressed on trastuzumab.

Original languageEnglish (US)
Pages (from-to)697-706
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume65
Issue number4
DOIs
StatePublished - Mar 1 2010

Fingerprint

Phosphatidylinositol 3-Kinases
Cells
Breast Neoplasms
Assays
Immunoblotting
Cell Proliferation
Phosphorylation
Cell proliferation
Cytotoxicity
Trastuzumab
SF 1126
In Vitro Techniques
Caspase 3
Agar
Phosphotransferases
Apoptosis
Growth
Proteins

Keywords

  • Drug resistance
  • Herceptin
  • PI3-kinase
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells. / Ozbay, Tuba; Durden, Donald L; Liu, Tongrui; O'Regan, Ruth M.; Nahta, Rita.

In: Cancer Chemotherapy and Pharmacology, Vol. 65, No. 4, 01.03.2010, p. 697-706.

Research output: Contribution to journalArticle

@article{d600229b5864427abe87ea685de16e94,
title = "In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells",
abstract = "Purpose: The purpose of the current study is to determine the in vitro cytotoxic effects of the novel pan-PI3-kinase inhibitor SF1126 in HER2-over-expressing breast cancer cells. Methods: Cell proliferation and cytotoxicity were examined by MTS colorimetric assay, FACS analysis, colony formation assay, and immunoblotting. Phosphoinositol-3-kinase signaling was assessed by immunoblotting for phosphorylated Akt. Combination effects of trastuzumab and SF1126 were examined in resistant cells by MTS and soft agar assay. Results: SF1126 inhibited proliferation, and induced G1 arrest and apoptosis of SKBR3 and BT474 parental and trastuzumab-resistant HER2-over-expressing cells. Colony formation was inhibited by SF1126, caspase 3 and PARP proteins were cleaved, and survivin was down-regulated. Inhibition of PI3-kinase was confirmed by reduced phosphorylation of Akt. Finally, the combination of SF1126 and trastuzumab synergistically inhibited proliferation of resistant cells, with SF1126-treated cells showing reduced anchorage- independent growth. Conclusions: These results provide evidence that a clinically relevant pan-PI-3 kinase inhibitor can reverse trastuzumab resistance in breast cancer cells, and support further study of PI3-kinase inhibitor SF1126 in HER2-over-expressing breast cancer cells, including those that have progressed on trastuzumab.",
keywords = "Drug resistance, Herceptin, PI3-kinase, Targeted therapy",
author = "Tuba Ozbay and Durden, {Donald L} and Tongrui Liu and O'Regan, {Ruth M.} and Rita Nahta",
year = "2010",
month = "3",
day = "1",
doi = "10.1007/s00280-009-1075-9",
language = "English (US)",
volume = "65",
pages = "697--706",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells

AU - Ozbay, Tuba

AU - Durden, Donald L

AU - Liu, Tongrui

AU - O'Regan, Ruth M.

AU - Nahta, Rita

PY - 2010/3/1

Y1 - 2010/3/1

N2 - Purpose: The purpose of the current study is to determine the in vitro cytotoxic effects of the novel pan-PI3-kinase inhibitor SF1126 in HER2-over-expressing breast cancer cells. Methods: Cell proliferation and cytotoxicity were examined by MTS colorimetric assay, FACS analysis, colony formation assay, and immunoblotting. Phosphoinositol-3-kinase signaling was assessed by immunoblotting for phosphorylated Akt. Combination effects of trastuzumab and SF1126 were examined in resistant cells by MTS and soft agar assay. Results: SF1126 inhibited proliferation, and induced G1 arrest and apoptosis of SKBR3 and BT474 parental and trastuzumab-resistant HER2-over-expressing cells. Colony formation was inhibited by SF1126, caspase 3 and PARP proteins were cleaved, and survivin was down-regulated. Inhibition of PI3-kinase was confirmed by reduced phosphorylation of Akt. Finally, the combination of SF1126 and trastuzumab synergistically inhibited proliferation of resistant cells, with SF1126-treated cells showing reduced anchorage- independent growth. Conclusions: These results provide evidence that a clinically relevant pan-PI-3 kinase inhibitor can reverse trastuzumab resistance in breast cancer cells, and support further study of PI3-kinase inhibitor SF1126 in HER2-over-expressing breast cancer cells, including those that have progressed on trastuzumab.

AB - Purpose: The purpose of the current study is to determine the in vitro cytotoxic effects of the novel pan-PI3-kinase inhibitor SF1126 in HER2-over-expressing breast cancer cells. Methods: Cell proliferation and cytotoxicity were examined by MTS colorimetric assay, FACS analysis, colony formation assay, and immunoblotting. Phosphoinositol-3-kinase signaling was assessed by immunoblotting for phosphorylated Akt. Combination effects of trastuzumab and SF1126 were examined in resistant cells by MTS and soft agar assay. Results: SF1126 inhibited proliferation, and induced G1 arrest and apoptosis of SKBR3 and BT474 parental and trastuzumab-resistant HER2-over-expressing cells. Colony formation was inhibited by SF1126, caspase 3 and PARP proteins were cleaved, and survivin was down-regulated. Inhibition of PI3-kinase was confirmed by reduced phosphorylation of Akt. Finally, the combination of SF1126 and trastuzumab synergistically inhibited proliferation of resistant cells, with SF1126-treated cells showing reduced anchorage- independent growth. Conclusions: These results provide evidence that a clinically relevant pan-PI-3 kinase inhibitor can reverse trastuzumab resistance in breast cancer cells, and support further study of PI3-kinase inhibitor SF1126 in HER2-over-expressing breast cancer cells, including those that have progressed on trastuzumab.

KW - Drug resistance

KW - Herceptin

KW - PI3-kinase

KW - Targeted therapy

UR - http://www.scopus.com/inward/record.url?scp=75749091464&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=75749091464&partnerID=8YFLogxK

U2 - 10.1007/s00280-009-1075-9

DO - 10.1007/s00280-009-1075-9

M3 - Article

VL - 65

SP - 697

EP - 706

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 4

ER -