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Vitamin K analog (compound 5) induces apoptosis in human hepatocellular carcinoma independent of the caspase pathway

Enokimura, Naoyukia; Shiraki, Katsuyaa; Kawakita, Tomoyukia; Saitou, Yukikoa; Inoue, Hidekazua; Okano, Hiroshia; Yamamoto, Norihikoa; Sugimoto, Kazushia; Carr, Brian I.b; Nakano, Takeshia

doi: 10.1097/01.cad.0000175583.78574.d7

A systemic vitamin K analog, compound 5 (Cpd 5), possesses the ability to inhibit cell growth of tumor cells. Therefore, we investigated the effect of Cpd 5 in human hepatocellular carcinoma (HCC) cell lines and evaluated its role in apoptosis. Human HCC cell lines were cultured and treated with Cpd 5. Apoptosis was assessed using DAPI staining and Annexin-V membrane staining. The expression of caspases, XIAP and Bcl-xL was also investigated. Cpd 5 decreased cell viability in a dose-dependent manner in two HCC cells (HLE and SK-Hep1) containing mutant p53, but not in the HepG2 cell line, which contained wild-type p53. Cpd 5-treated HLE and SK-Hep1 cells showed typical apoptotic features, nuclear condensation and nuclear fragmentation upon DAPI staining. Positive membranous staining for Annexin-V was also seen in these cells. Both caspase-8 and caspase-3 activities were up-regulated slightly. Pro-caspase-8 protein levels decreased slightly in both cells. Although the expression of Bcl-xL was not influenced by Cpd 5, that of XIAP decreased in HLE cells. However, the pan-caspase inhibitor, zVAD, could not significantly prevent Cpd 5-induced apoptosis and Cpd 5 could not augment TRAIL-induced apoptosis. These results demonstrate that Cpd 5 induced apoptosis in human HCC cell lines, mainly independently of caspase activities. This may contribute to its highly potent cytotoxicity toward HCC cells.

aFirst Department of Internal Medicine, Mie University School of Medicine, Mie, Japan

bLiver Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Correspondence to K. Shiraki, First Department of Internal Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan

Tel: +81 59 231 5115; fax: +81 59 231 5201;


Received 28 May 2005 Accepted 13 June 2005

© 2005 Lippincott Williams & Wilkins, Inc.