BACKGROUND. Honokiol, a soluble nontoxic natural product derived from Magnolia spp., has been shown to induce apoptosis in malignant cells. The effect of honokiol and the combined therapy with docetaxel on prostate cancer (PCa) growth and bone metastasis was investigated in experimental models. METHODS. The in vitro proapoptotic effects of honokiol on human androgen-dependent and -independent PCa, bone marrow, bone marrow-derived endothelial, and prostate stroma cells were investigated. Honokiol-induced activation of caspases was evaluated by Western blot and FACS analysis. To confirm the cytotoxicity of honokiol, mice bone was inoculated in vivo with androgen-independent PCa, C4-2 cells and the effects of honokiol and/or docetaxel on PCa growth in bone were evaluated. Daily honokiol (100 mg/kg) and/or weekly docetaxel (5 mg/kg) were injected intraperitoneally for 6 weeks. PCa growth In mouse bone was evaluated by radiography, serum prostate-specific antigen (PSA) and tissue immunohistochemistry. RESULTS. Honokiol induced apoptosis in all cell lines tested. In PCa cells honokiol induced apoptosis via the activation of caspases 3, 8, and 9 and the cleavage of poly-adenosine diphosphate ribose polymerase in a dose- and time-dependent manner. Honokiol was shown to inhibit the growth and depress serum PSA in mice harboring C4-2 xenografts in the skeleton and the combination with docetaxel showed additive effects that inhibited further growth without evidence of systemic toxicity. Immunohistochemical staining confirmed honokiol exhibited growth-inhibitory, apoptotic, and antiangiogenic effects on PCa xenografts. CONCLUSIONS. The combination of honokiol and low-dose docetaxel may be used to improve patient outcome in androgen-independent prostate cancer with bone metastasis. © 2007 American Cancer Society.