Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells

Abstract

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. Cancer 2007. © 2007 American Cancer Society.

Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity

“…Similarly, i.p. injection of 100 mg honokiol/kg body weight sensitized androgen-independent C4-2 human prostate cancer cells inoculated in mouse bilateral tibia to docetaxel without causing any systemic toxicity (46). Unpublished studies from our laboratory also indicate that oral gavage of 2 mg honokiol per mouse (thrice a week) statistically significantly inhibits the growth of PC-3 xenografts in male nude mice without causing weight loss or any other side effects.…”

Anti-Cancer Effect of the Combination of Thiacremonone and Docetaxel by Inactivation of NF-κB in Human Cancer Cells

“…For examples, resveratrol or propolis in combination with vinorelbine showed a potential useful treatment for DU145 prostate cancer via the increase cell cycle control reinforcing cell growth inhibition (Scifo et al, 2006). Shigemura et al reported that honokiol, a natural plant product, enhanced inhibition of the bone metastatic growth of human prostate cancer cells by docetaxcel (Shigemura et al, 2007). In addition, the combination of docetaxel, vinorelbine and oral estramustine was a well-tolerated regimen with high biochemical and objective response rates in patients with androgen-resistant prostate cancer (ARPC) (Rosenberg et al, 2009).…”

Plant-derived anticancer agents: a promising treatment for bone metastasis

“…Immunohistochemical analysis of the tumor in mouse tibia showed that honokiol plus docetaxel treatment markedly decreased cell proliferation and vascular density, and increased apoptosis compared with vehicle-treated mice. 36 These results suggest that honokiol is a promising molecule that could be used as an adjuvant treatment in combination with low-dose docetaxel for the treatment of hormone-refractory prostate cancer and its bone metastases. Honokiol appears to be well tolerated with low toxicity.…”

“…35 Honokiol also has anti-inflammatory effects as it decreases the expression of inflammatory mediators, inflammatory genes and the proliferation of lymphocytes induced by lipopolysaccharide. 36 In bone metastasis, Shigemura et al 36 tested the effects of honokiol alone and in combination with docetaxel, a secondgeneration taxane that is currently used in therapy for metastatic prostate cancer on human prostate tumor xenografts in the tibia of mice. 36 Honokiol induced the apoptosis of human androgen-dependent and -independent prostate cancer cells Plant anticancer agents and bone metastasis P Juá rez as well as of bone marrow, bone marrow-derived endothelial and prostate stromal cells, via the activation of caspase-3, -8 and -9 in a dose-and time-dependent manner.…”

“…36 In bone metastasis, Shigemura et al 36 tested the effects of honokiol alone and in combination with docetaxel, a secondgeneration taxane that is currently used in therapy for metastatic prostate cancer on human prostate tumor xenografts in the tibia of mice. 36 Honokiol induced the apoptosis of human androgen-dependent and -independent prostate cancer cells Plant anticancer agents and bone metastasis P Juá rez as well as of bone marrow, bone marrow-derived endothelial and prostate stromal cells, via the activation of caspase-3, -8 and -9 in a dose-and time-dependent manner. The antitumor effects of honokiol alone or in combination with docetaxel were evaluated in vivo in mice harboring tumors from C4-2 prostate cancer cells and treated with honokiol (100 mg kg À 1 per day) alone or in combination with docetaxel (5 mg kg À 1 per week) for 6 weeks.…”