Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts.
BACKGROUND
Midkine (MK) is a heparin-binding growth factor that promotes the growth, migration, and survival of various cells. Its overexpression has been observed in many human malignancies, making it an attractive therapeutic target.


METHODS
We established a human midkine blockade system involving RNA interference.


RESULTS
The synthetic small interfering RNA (siRNA) targeting human midkine almost completely inhibited the secretion of midkine by a human prostate cancer cell line, PC-3, and consequently suppressed the proliferation and anchorage-independent growth of the transfected cells. The midkine siRNA, together with atelocollagen, significantly suppressed the growth of PC-3 tumors, which had been subcutaneously xenografted. These inhibitory effects of midkine siRNA were augmented by combinational treatment with a chemotherapeutic, paclitaxel (PTX), both in vitro and in vivo. The dose of PTX (12 mg/kg) used for the combinational treatment did not cause leukopenia or liver damage, which are often reported as serious adverse effects of PTX. The effect of the combination on tumor growth was comparable with that of PTX alone at higher doses that have exhibited severe adverse effects. Midkine siRNA suppressed mainly cell proliferation and slightly angiogenesis, whereas PTX enhanced apoptosis and slightly suppressed angiogenesis. The combination treatment was particularly effective for suppression of angiogenesis; consequently, it had striking effects on all aspects (proliferation, apoptosis, and angiogenesis).


CONCLUSIONS
We established a novel and safe cancer therapy strategy involving midkine siRNA combined with PTX, with less adverse effects.
Takei
Yoshifumi
Y
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan. takei@med.nagoya-u.ac.jp
Kadomatsu
Kenji
K
Goto
Tatsunori
T
Muramatsu
Takashi
T
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000078792:Midkine; D017239:Paclitaxel / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D034741:RNA, Small Interfering; D000078792:Midkine; D017239:Paclitaxel