TY - JOUR
T1 - Vitamin K analog (compound 5) induces apoptosis in human hepatocellular carcinoma independent of the caspase pathway
AU - Enokimura, Naoyuki
AU - Shiraki, Katsuya
AU - Kawakita, Tomoyuki
AU - Saitou, Yukiko
AU - Inoue, Hidekazu
AU - Okano, Hiroshi
AU - Yamamoto, Norihiko
AU - Sugimoto, Kazushi
AU - Carr, Brian I.
AU - Nakano, Takeshi
PY - 2005/9
Y1 - 2005/9
N2 - 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-x L 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.
AB - 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-x L 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.
KW - Apoptosis
KW - Caspase-independent pathway
KW - Compound 5
KW - Human hepatocellular carcinoma
KW - Vitamin K
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UR - http://www.scopus.com/inward/citedby.url?scp=24044491266&partnerID=8YFLogxK
U2 - 10.1097/01.cad.0000175583.78574.d7
DO - 10.1097/01.cad.0000175583.78574.d7
M3 - Article
C2 - 16096431
AN - SCOPUS:24044491266
VL - 16
SP - 837
EP - 844
JO - Anti-Cancer Drugs
JF - Anti-Cancer Drugs
SN - 0959-4973
IS - 8
ER -