Recently, the synthesized octahedral Pt(IV) compound
trans,cis-Pt(acetato)2Cl2(1,4-butanediamine), K101, showed potent anti-
tumor activity in vitro and in vivo. For the further investigation of K101-induced anti-
cancer activity, we tested cytotoxicity against various
cancer cell lines and performed the histoculture
drug response assay (HDRA) against human
colorectal tumor tissues in vitro. We investigated the signaling pathway of K101-induced apoptosis via expression of p53 and ERK1/2 in the human colon cell line HCT116. The cytotoxicity and the three-dimensional HDRA of K101 were evaluated using the MTT assay. To study the K101-induced apoptosis pathway, we performed FACS analysis and immunoblotting of p53, p21, Bax, Fas and ERK1/2 in HCT116 cells treated with or without K101. The cytotoxic IC50 values of K101 ranged from 1.15 to 2.38 micromol/l, compared to
cisplatin ranging from 2.13 to 13.1 micromol/l. Among several
cancer cell lines, K101 showed greater potency than
cisplatin in
colon cancer cell lines. In the HDRA, K101 showed 80.0-91.4% efficacy rates compared with 48.6% for
cisplatin against
colorectal cancer patient tissues. In the signaling pathway, the expression of p53 and phospho-ERK1/2 was increased in a time-dependent manner by treatment with K101 in the HCT116 cells. When K101 was treated with
MEK inhibitor
U0126, the cell death rate was increased. The octahedral Pt(IV) complex K101 could be an attractive candidate as a chemotherapeutic agent against
colon cancer. ERK1/2 activation and the p53 pathway may play significant functions in mediating K101-induced apoptosis in human
colon cancer cells.