Abstract
Abstract Perifosine, a novel phosphatidylinositol-3-kinase (PI3K)/Akt signaling inhibitor is currently being tested in several phase II/III trials for treatment of major human cancers. However, the efficacy of perifosine in human gastric cancer has not been established. As Akt is known to be highly activated in gastric cancer, we investigated the antitumor effect and gene expression patterns of perifosine on gastric cancer cells. The antitumor efficacy was examined in 25 gastric cancer cell lines (4 from ATCC, 4 from JCRB, 8 from KCBL, and 9 cell lines established from Korean gastric cancer patients at the Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul, Korea). Several in vitro assays {MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphnyltetrazolium bromide] assay, western blotting for Akt pathway, apoptosis, cell cycle and microarray analysis} were used to assess the cytotoxic effect of 5-fluorouracil (5-FU) and perifosine. In vivo response study of human gastric cancer cell line was measured after perifosine treatment. Perifosine inhibited gastric cancer cell growth as a dose and time-dependent manner with the median 1.09 μmol/L of IC50 (range 0.2-5.8 μmol/L). 5-FU alone inhibited cell growth with the median 11.1 μmol/L of IC50 (range 2.6 to 380 μmol/L). For the combination effect, perifosine and 5-FU were synergistic in 14 (56%) cell lines and antagonistic in 8 (32%) cell lines. To clarify the different mechanism of synergistic and antagonistic effect, we selected one synergistic (YCC2, 5-FU IC 50= 11.1) and antagonistic cell lines (SNU 628, 5-FU IC 50=57.2) among those relatively 5-FU insensitive cell lines. In terms of signal pathway, perifosine inhibited pAkt and pERK1/2 expression and it activated pJNK expression. However, this change was not seen in the antagonistic cell line (SNU 638). In addition, for the perifosine and 5-FU combination, these patterns were also similarly demonstrated. Apoptotic molecule, cleaved PARP was also increased as a dose and time dependent manner. Then, we compared gene expression patterns between 6 perifosine-sensitive and 3 perifosine-resistant cell lines and identified 122 genes related to perifosine sensitivity (by 4-folds, P<0.05) including 49 up-regulated and 48 down-regulated known genes in the resistant cells. Antitumor efficacy of perifosine monotherapy and combination with 5-FU derivative (capecitabine) were treated for YCC2 tumor bearing xenograft mice. Perifosine monotherapy demonstrated moderate antitumor activity. The combination of both agents produced a more prominent antitumor response as compared to monotherapy. Taken together, in gastric cancer cells, perifosine demonstrated antitumor activity and enhances the efficacy of 5-FU even in taxane-resistant cancer cell lines. Current data provide strong support for further development of this combination in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2236. doi:1538-7445.AM2012-2236
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