title: Combating trastuzumab resistance by targeting thioredoxin-1/PTEN interaction.
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.
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran.
authors.forename: Akram
authors.initials: A
authors.lastname: Sadeghirizi
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran. ryazadan@ut.ac.ir.
authors.forename: Razieh
authors.initials: R
authors.lastname: Yazdanparast
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran.
authors.forename: Safiyeh
authors.initials: S
authors.lastname: Aghazadeh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004220:Disulfides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D007093:Imidazoles; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D013879:Thioredoxins; D000068878:Trastuzumab; C412893:1-methylpropyl-2-imidazolyl disulfide
keywords: Breast cancer; Her2; PTEN; Thioredoxin-1; Trastuzumab resistance