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¹ Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan and ² Laboratory of Molecular Growth and Regulation, The National Institute of Child Health and Human Development, NIH, Bethesda, Maryland

Requests for reprints: Tomonori Uno, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-Monguchi-cho, Kisshoin, Minami, Kyoto 601-8550, Japan. Phone: 81-75-321-9169; Fax: 81-75-321-9038; E-mail: t.uno{at}po.nippon-shinyaku.co.jp

NS-9 is a complex of polyinosinic-polycytidylic acid and a novel cationic liposome, LIC-101. The complex has strong cytotoxic activity against tumor cells derived from epithelial or fibroblastic cells. We have investigated the mechanism of the cytotoxic activity of NS-9 using knockdown cells in which the expression of proteins of interest was inhibited by RNA interference. NS-9 showed strong cytotoxic activity against knockdown cells with reduced expression of double-stranded RNA-dependent protein kinase, RNase L, or IFN-/ß receptor, but showed no cytotoxic activity against IFN regulatory factor-3 (IRF3) knockdown cells. In IRF3-knockdown cells, NS-9 also did not induce either the DNA fragmentation or the rRNA degradation observed in negative control cells. We conclude that IRF3 plays a crucial role in the cytotoxic activity of NS-9 against tumor cells, whereas RNA-dependent protein kinase, RNase L, or type I IFNs are not important for its activity.

Key Words: dsRNA • apoptosis • IRF3 • TLR3 • cationic liposome • poly(I):poly(C)

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³ Supplemental material is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 11/29/04; revised 2/17/05; accepted 3/16/05.