Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells.
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.
Shigemura
Katsumi
K
Molecular Urology and Therapeutics Program, Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
Arbiser
Jack L
JL
Sun
Shi-Yong
SY
Zayzafoon
Majd
M
Johnstone
Peter A S
PA
Fujisawa
Masato
M
Gotoh
Akinobu
A
Weksler
Babette
B
Zhau
Haiyen E
HE
Chung
Leland W K
LW
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000556:secondary; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D017705:Lignans / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011859:Radiography; D043823:Taxoids / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000498:Allyl Compounds; D010636:Phenols
D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D020169:Caspases; D000077143:Docetaxel; D004365:Drugs, Chinese Herbal; D017705:Lignans; D017430:Prostate-Specific Antigen; D043823:Taxoids; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols