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Tumor Biology
Published in: Tumor Biology 5/2016

01-05-2016 | Original Article

Combating trastuzumab resistance by targeting thioredoxin-1/PTEN interaction

Authors: Akram Sadeghirizi, Razieh Yazdanparast, Safiyeh Aghazadeh

Published in: Tumor Biology | Issue 5/2016

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Abstract

Trastuzumab is by far the drug of choice for treatment of human epidermal growth factor receptor 2 (Her2) overexpressing breast cancer patients. However, frequently, the therapy remains ineffective due to the induced drug resistance. In spite of various reported mechanisms, we hypothesize that the acquired resistance to trastuzumab might be attributed to the failure of the drug to activate phosphatase and tensin homolog (PTEN) mainly due to the high level of reduced thioredoxin-1 protein among the resistant cells. In the present study, the effect(s) of PX-12, a Trx-1 inhibitor, was examined on proliferation of breast cancer cells which are unresponsive to trastuzumab. Treatment of the cells with PX-12 (5 μM) and trastuzumab (10 μg/ml) reduced cells viabilities, p-Akt, and Bcl2 levels while increasing the levels of reactive oxygen species (ROS) and p-JNK with consequent higher levels of G1 arrest and apoptosis among the resistant cells compared to parental trastuzumab sensitive cells. The most significant observation was that PX-12/trastuzumab co-treatment enhanced the cell membrane localization of PTEN which is believed to be the active biological form of the signal. Our data confirmed that Trx-1 inhibition is required for chemosensitization of resistant breast cancer cells to anti-Her2 therapy, and this approach might offer an alternative clinical strategy for preventing acquired resistance.
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Metadata
Title
Combating trastuzumab resistance by targeting thioredoxin-1/PTEN interaction
Authors
Akram Sadeghirizi
Razieh Yazdanparast
Safiyeh Aghazadeh
Publication date
01-05-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 5/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4424-9

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