Therapeutic Discovery Plumbagin Inhibits Osteoclastogenesis and Reduces Human Breast Cancer-Induced Osteolytic Bone Metastasis in Mice through Suppression of RANKL Signaling

Bone loss is one of the major complications of advanced cancers such as breast cancer, prostate cancer, and multiple myeloma; agents that can suppress this bone loss have therapeutic potential. Extensive research within the last decade has revealed that RANKL, amemberof the tumornecrosis factor superfamily, plays amajor role in cancer-associated bone resorption and thus is a therapeutic target. We investigated the potential of vitamin K3 analogue plumbagin (derived from Chitrak, an Ayurvedic medicinal plant) to modulate RANKL signaling, osteoclastogenesis, and breast cancer-induced osteolysis. Plumbagin suppressed RANKL-induced NF-kB activation inmousemonocytes, anosteoclast precursor cell, through sequential inhibitionofactivationof IkBakinase, IkBa phosphorylation, and IkBa degradation. Plumbagin also suppressed differentiation of these cells into osteoclasts induced either by RANKL or by human breast cancer or human multiple myeloma cells. When examined for its ability to prevent human breast cancer-induced bone loss in animals, plumbagin (2mg/kg body weight) administered via the intraperitoneal route significantly decreased osteolytic lesions, resulting in preservation of bone volume in nudemice bearing humanbreast tumors.Overall, our results indicate that plumbagin, a vitamin K analogue, is a potent inhibitor of osteoclastogenesis induced by tumor cells and of breast cancerinduced osteolytic metastasis through suppression of RANKL signaling. Mol Cancer Ther; 1–10. 2011 AACR.