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, p21(Cip1), and p27(Kip1) and decreases in the
Inhibitor of Apoptosis Protein levels and
NF-kappaB 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.