Inhibition of cancer cell growth by polyinosinic-polycytidylic acid/cationic liposome complex: a new biological activity.
A complex of polyinosinic-polycytidylic acid [poly(I) x poly(C)] and cationic liposome (LIC) inhibited the growth of many tumor cell lines at low concentration in vitro, but poly(I) x poly(C) alone had no such antiproliferative effect. The IC50 values of LIC against the tumor cells ranged from 0.1 to 1000 ng/ml. LIC had strong cytotoxic effects on malignant cells of epithelial and fibroblastic origin from various tissues and was also effective against Adriamycin-resistant tumor cells. LIC did not significantly affect the growth of lymphoma cells, leukemia cells, normal diploid fibroblasts, or primary liver cells at concentrations up to 10 microg/ml. The mechanism of the antiproliferative effect of LIC against malignant cells was the induction of apoptosis. LIC induced the fragmentation of nuclear DNA and the degradation of rRNA in tumor cells. The DNA fragmentation occurred within 1-5 h after the addition of LIC, and both the fragmentation and the inhibition of cancer-cell growth were suppressed by a nuclease inhibitor. In contrast, caspase inhibitors did not affect the antiproliferative activity of LIC. These results suggest that LIC induced apoptosis in malignant cells through the direct activation of nucleases and not through the activation of caspases. LIC reduced the incidence and the size of metastatic liver-cancer tumors in two different mouse metastatic liver-cancer models using human colon carcinoma cells. Histochemical analysis revealed that the KM12-HX cells in the tumor nodules were undergoing apoptosis; therefore, LIC also induced the apoptosis of tumor cells in vivo. In these animal models, LIC caused no observed changes in normal hepatocytes.
Hirabayashi
K
K
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan. k.hirabayashi@po.nippon-shinyaku.co.jp
Yano
J
J
Inoue
T
T
Yamaguchi
T
T
Tanigawara
K
K
Smyth
G E
GE
Ishiyama
K
K
Ohgi
T
T
Kimura
K
K
Irimura
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D008081:Liposomes; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008845:Microinjections; D011070:Poly I-C / Q000493:pharmacokinetics / Q000494:pharmacology*; D012335:RNA, Ribosomal / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D008081:Liposomes; D012335:RNA, Ribosomal; D011070:Poly I-C