FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft

Background: A unique immunosuppressant, FTY720, selectively induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. The potential that this unique mechanism could provide anticancer potential by inducing apoptosis in the human renal cancer cell line, ACHN, which is resistant to cisplatin, and its molecular pathway was investigated. Materials and Methods: The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and flow cytometty. Apoptosis assay, including TUNEL staining, electron microscopy and DNA electrophoresis, was performed and the molecularpathway of FTY720 was evaluated by real time RTPCR and Western blot. The in vivo effect of FTY720 was evaluated using a murine zenograft model. Results: The susceptibility to FTY720 was significantly higher in ACHN cancer cells than in normal renal tubular cells (HK-2) at a concentration of less than 30 mu M, while the susceptibility to cisplatin was even higher in HK-2 than in A CHN. Cancer cells treated with FTY720 showed findings typical of apoptosis with highly condensed nuclear chromatin and fragmented nuclei. The molecular analysis revealed that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway, and that inhibition of extracellular signal-regulated kinase (ERK) activity was involved in its underlying mechanism of action. FTY720 treatment significantly prevented in vivo tumor growth without any severe adverse reactions, while cisplatin treatment did not inhibit tumor growth despite exhibiting severe side-effects. Conclusion: FTY720 may be a promising candidate for a new anticancer therapy of renal cancer.