Tetrathiomolybdate reduces bone cancer pain and tumor-associated osteoclast activation through copper-dependent LOX signaling.

Bone cancer pain (BCP) affects most patients with bone metastases and is poorly managed by current analgesics. This study evaluated tetrathiomolybdate (TTM), a clinical copper chelator, for its potential to simultaneously target osteoclast activation and copper-dependent tumor growth in BCP. Using a mouse model with intrafemoral Lewis lung carcinoma cells, TTM (20-40 mg·kg-1 daily) significantly reduced mechanical allodynia and thermal hyperalgesia, even when treatment began after pain establishment. TTM suppressed osteoclast differentiation markers in bone tissue and bone marrow-derived macrophages cultures. It also directly inhibited tumor cell viability in vitro and reduced tumor burden in vivo by 43%. Mechanistically, TTM downregulated lysyl oxidase (LOX) in tumor bone, and exogenous LOX partially reversed the inhibitory effect of TTM on osteoclasts differentiation. These findings suggest that TTM alleviates BCP potentially through inhibition of copper-dependent tumor progression and attenuation of LOX-associated osteoclast activation. Our results support further investigation of copper-dependent signaling pathways as potential modulators of tumor-associated bone destruction and cancer-induced pain.