6P Antioxidant N-Acetylcysteine Inhibits Cancer-Induced Osteolysis in Mouse Models of Breast-To-Bone Metastasis

Abstract

ABSTRACT Reactive oxygen species (ROS) are known to play a crucial role in the maturation and activation of bone-resorbing osteoclast cells. In support of this, several recent reports have shown that antioxidants suppress bone resorption in mouse models of osteoporosis. In this study, we examined the impact of the orally available antioxidant N-acetylcysteine (NAC) in mouse models of primary tumour growth, metastasis and cancer-induced osteolysis using grafted 4T1.2 (mouse) and MDA-MB-231 (human) cell lines. Tumour growth rates for both lines grafted at the mammary fat pad site were similar for Placebo (water) treated mice as well as the three doses of NAC examined (ranging 0.1 to 1 gm/kg/day). However when MDA-MB-231 cells were directly inoculated into the tibia of mice, a statistically significant suppression of onset of osteolysis was observed for all three dosing schedules. A similar trend was evident for 4T1.2 cells inoculated into the tibia; however this did not reach statistical significance. For both models, zoledronic acid (a bisphosphonate), had a significant impact on suppressing osteolysis and supplementation with NAC had an additive, positive effect on slowing progression of osteolysis. In conclusion, evidence for beneficial effects of antioxidant NAC was demonstrated in our selected mouse models, suggesting that antioxidants may be beneficial in human breast cancer treatment and cancer-induced osteolysis. We are currently performing antioxidant pharmacodynamic assays on mouse tissues (including bone marrow cells flushed from tibia) for non-tumour challenged mice following dosing with a range of high-dose oral antioxidant formulations. This includes natural product formulations. Those with optimal activity will be subsequently evaluated in the cancer induced osteolysis models described above. Disclosure All authors have declared no conflicts of interest.