Targeting Osteoclastogenesis: Sabutoclax reduces tumor-associated osteolysis and tumor burden within the bone microenvironment.

Bone metastasis is a major complication of breast cancer, characterized by osteolytic destruction mediated by excessive osteoclast activation. Current anti-resorptive therapies primarily target osteoclasts but have limited impact on the tumor-bone microenvironment vicious cycle that drives bone destruction. This study evaluated the therapeutic efficacy of a novel pan-B-cell lymphoma 2 inhibitor, Sabutoclax, in a breast cancer-induced model osteolysis and explored potential mechanisms associated with its effects. At the cellular level, we assessed the effects of Sabutoclax on the proliferation, invasion, migration, and apoptosis of cancer cells. We observed that Sabutoclax treatment was associated with inhibition of RANKL-induced osteoclast differentiation, RANKL-induced acid secretion, F-actin ring formation, osteoclast bone resorption function, reactive oxygen species (ROS) production, mitogen-activated protein kinase/extracellular signal-regulated kinase signaling, as well as reduced nuclear translocation and expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). In the animal experiment, an orthotopic breast cancer osteolysis model in the tibia of nude mice was established. The in vivo efficacy of Sabutoclax was evaluated. This study found that Sabutoclax effectively prevents breast cancer-induced osteolysis, which may involve a dual mechanism, suppressing breast cancer cell functions and targeting osteoclast differentiation and acid secretion. And the present study only shows that Sabutoclax is associated with ROS reduction, mitochondrial perturbation, and suppression of ERK/NFATc1 signaling. Sabutoclax treatment was associated with both decreased protein expression and reduced nuclear translocation of NFATc1. Future studies could focus on comprehensive evaluation of its pharmacokinetic properties, systemic toxicity, and therapeutic efficacy in more clinically relevant metastatic models to establish its potential application in breast cancer-induced osteolytic bone destruction.