Morpholino antisense oligomer targeting human midkine: its application for cancer therapy.
Overexpression of a heparin-binding growth factor, midkine (MK), has been observed in many malignancies, making it an attractive therapeutic target. We used morpholino antisense oligomers to downregulate human MK expression in human prostate (PC-3) and colon carcinoma (SW620) cells, and determined the practical advantages of this anticancer therapeutic. Morpholino antisense oligomers directed against MK caused a dramatic and sequence-specific decrease of the target protein level, resulting in the inhibition of growth and anchorage-independent growth of the transfected cells. Furthermore, MK morpholino antisense oligomers exhibited a significant anticancer effect in the PC-3- and SW620-xenograft models. In comparison with phosphorothioate-modified oligodeoxynucleotide, morpholino oligomers showed 2 major advantages, stability and non-toxicity. MALDI-TOF mass spectrometric analysis showed that morpholino antisense oligomers were completely stable in the presence of serum nuclease(s). Serological examinations demonstrated no toxicity of MK morpholino antisense oligomers. Our study indicates that inhibition of MK expression by morpholino antisense oligomer is a promising novel and safe therapeutic strategy for cancers.
Takei
Yoshifumi
Y
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan. takei@med.nagoya-u.ac.jp
Kadomatsu
Kenji
K
Yuasa
Kanako
K
Sato
Waichi
W
Muramatsu
Takashi
T
D000818:Animals; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000078792:Midkine; D009025:Morpholines; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D009414:Nerve Growth Factors; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000473:pathology*; D014162:Transfection; D014183:Transplantation, Heterologous
D016207:Cytokines; D009025:Morpholines; D009414:Nerve Growth Factors; D016376:Oligonucleotides, Antisense; D000078792:Midkine