NOSH-aspirin (NBS-1120) inhibits estrogen receptor negative breast cancer in vitro and in vivo by modulating redox-sensitive signaling pathways.

ABSTRACT

Estrogen receptor (ER)-negative breast cancers are known to be aggressive and unresponsive to anti-estrogen therapy, and triple negative breast cancers are associated with poor prognosis and metastasis. Thus, new targeted therapies are needed. FOXM1 is abundantly expressed in human cancers and implicated in protecting tumor cells from oxidative stress by reducing the levels of intracellular reactive oxygen species (ROS). Aspirin, a prototypical anti-cancer agent with deleterious side effects, has been modified to release nitric oxide and hydrogen sulfide, called NOSH-aspirin (NOSH-ASA), generating a 'safer' class of new anti-inflammatory agents. We evaluated NOSH-ASA against (ER)-negative breast cancer using cell lines and a xenograft mouse model. NOSH-ASA strongly inhibited growth of MDA-MB-231 and SKBR3 breast cancer cells with low IC50s of 90{plus minus}5 and 82{plus minus}5 nM, respectively, with marginal effects on a normal breast epithelial cell line. NOSH-ASA inhibited cell proliferation, caused G0/G1 phase arrest, increased apoptosis, and was associated with increases in ROS. In MDA-MB-231 cell xenografts, NOSH-ASA reduced tumor size markedly, which was associated with reduced proliferation (decreased PCNA expression), induction of apoptosis (increased TUNEL positive cells), and increased ROS, while NF-kB and FoxM1 that were high in untreated xenografts were significantly reduced. mRNA data for FoxM1, p21 and CyclinD1 corroborated with the respective protein expressions and arrest of cells. Taken together, these molecular events contribute to NOSH-ASA mediated growth inhibition and apoptotic death of (ER)-negative breast cells in vitro and in vivo. Additionally, as a ROS-inducer and FOXM1-inhibitor, NOSH-ASA has potential as a targeted therapy. Significance Statement In this investigation, we examined the cellular effects and xenograft tumor inhibitory potential of NOSH-aspirin, an NO and H2S-donating hybrid, against ER-negative breast cancer, which currently lacks effective therapeutic options. The induction of reactive oxygen species and subsequent downregulation of FOXM1 represents a plausible mechanism contributing to the observed decrease in cell proliferation and concurrent increase in apoptosis. NOSH-ASA demonstrated a remarkable reduction in tumor size by 90% without inducing any observable gross toxicity, underscoring its promising translational potential.