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Cancer Chemotherapy and Pharmacology

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Open Access 01-03-2010 | Original Article

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

Authors: Tuba Ozbay, Donald L. Durden, Tongrui Liu, Ruth M. O’Regan, Rita Nahta

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2010

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.

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Title: In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells
Authors: Tuba Ozbay
Donald L. Durden
Tongrui Liu
Ruth M. O’Regan
Rita Nahta
Publication date: 01-03-2010
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1075-9

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Abstract

Purpose

Methods

Results

Conclusions

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