Preclinical study

Breast Cancer Research and Treatment

, Volume 121, Issue 2, pp 311-321

First online:

Elesclomol, counteracted by Akt survival signaling, enhances the apoptotic effect of chemotherapy drugs in breast cancer cells

  • Ying QuAffiliated withDepartment of Molecular Oncology, John Wayne Cancer Institute, Saint John’s Health CenterDepartment of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine
  • , Jinhua WangAffiliated withDepartment of Molecular Oncology, John Wayne Cancer Institute, Saint John’s Health Center
  • , Myung-Shin SimAffiliated withDepartment of Biostatistics, John Wayne Cancer Institute, Saint John’s Health Center
  • , Bingya LiuAffiliated withDepartment of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine
  • , Armando GiulianoAffiliated withDepartment of Molecular Oncology, John Wayne Cancer Institute, Saint John’s Health Center
  • , James BarsoumAffiliated withSynta Pharmaceuticals Corporation
  • , Xiaojiang CuiAffiliated withDepartment of Molecular Oncology, John Wayne Cancer Institute, Saint John’s Health Center Email author 

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Abstract

Elesclomol is a small-molecule investigational agent that selectively induces apoptosis in cancer cells by increasing oxidative stress. Elesclomol plus paclitaxel was shown to prolong progression-free survival compared with paclitaxel alone in a phase II clinical trial in patients with metastatic melanoma. However, the therapeutic potential of elesclomol in human breast cancer is unknown, and the signaling mechanism underlying the elesclomol effect is unclear. Here, we show that elesclomol alone modestly inhibited the growth of human breast cancer cells but not normal breast epithelial cells. Elesclomol potentiated doxorubicin- or paclitaxel-induced apoptosis and suppression of breast cancer cell growth. While both c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase were activated by elesclomol, elesclomol-induced apoptosis was only in part mediated by JNK1. The additive effect of elesclomol on chemotherapy drug-induced apoptosis was associated with increases in cleaved caspase-3, p21Cip1, and p27Kip1 and decreases in the Inhibitor of Apoptosis Protein levels and NF-κB activity. We also found that Akt/Hsp70 survival signaling was induced by elesclomol, which may reflect a cellular feedback mechanism. Blockade of Akt activation using a small-molecule inhibitor enhanced elesclomol-elicited apoptosis, while expression of a hyperactive Akt abolished the elesclomol effect. These data suggest that elesclomol’s interaction with conventional chemotherapeutic and Akt-targeting agents may be exploited to induce apoptosis in breast cancer cells, and clinical trials of combined treatment of elesclomol and chemotherapy drugs or Akt-targeting agents in breast cancer patients, especially the estrogen receptor negative subgroup, may be warranted.

Keywords

Akt Apoptosis Chemotherapy Elesclomol JNK Reactive oxygen species