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CDA-II,a urinary preparation,induces growth arrest and apoptosis of human leukemia cells through inactivation of nuclear factor-kappaB in a caspase-dependent manner
Authors:Jian Huang  Min YangHui Liu  Jie Jin
Affiliation:Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, #79 Qingchun Road, Hangzhou, Zhejiang 310003, People’s Republic of China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang Province, #79 Qingchun Road, Hangzhou, Zhejiang 310003, People’s Republic of China; Key Lab of Combined Muti-organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, #79 Qingchun Road, Hangzhou, Zhejiang 310003, People’s Republic of China
Abstract:CDA-II (cell differentiation agent II) was a urinary preparation, isolated from healthy human urine. We determined the anticancer activity of CDA-II using human acute myeloid leukemia (AML) cell lines, K562, Kasumi-1 and KG-1. An in vitro cytotoxicity assay showed that CDA-II exhibited growth arrest in leukemic cells, while it did not induce cytotoxicity in normal peripheral blood monouclear cells (PBMCs). In vivo studies using the Kasumi-1 xenografted SCID mouse model showed tumor inhibition rate were increased and the survival time were prolonged in a dose-dependent manner, without any significant toxicity on mice body. Depolarized mitochondrial membranes and the activation of caspase-3, 9 as well as PARP were found in leukemic cells treated with CDA-II for 6–24 h. We further found NF-κB nuclear translocation were prevented by CDA-II treatment, which therefore inactivated NF-κB and down-regulated its target genes expression, including Bcl-2/Bax ratio, Mcl-1 and XIAP. The caspase-3 inhibitor Z-DEVD-FMK inhibited CDA-II-induced apoptosis and CDA-II combined with NF-κB inhibitor PDTC significantly increased the apoptotic rate of leukemic cells. We concluded that CDA-II potently induced caspase-dependent leukemia-specific apoptosis in leukemic cells mediated through inactivation of NF-κB, involving in Bcl-2 family and XIAP, which has no cytotoxicity on normal cells.
Keywords:CDA-II, cell differentiation agent II   AML, acute myeloid leukemia   NF-κB, nuclear factor-kappaB   PARP, poly(ADP-ribose) polymerase   XIAP, X-linked inhibitor of apoptosis protein   MTT, 3-(4,5-dimethylthiazol-2&ndash  yl)-2,5-diphenyl-tetrazolium bromide   JC-1, 5,5&prime  ,6,6&prime  -tetrachloro-1,1&prime  ,3,3&prime  -tetraethylben-Zimidazol-carbocyanineiodide   IC50, 50% inhibitory concentration   PBMCs, peripheral blood monouclear cells   SCID, serious combined immuno-deficiency disease   RTV, relative tumor volume   ΔΨm, mitochondrial membrane potential   OS, overall survival
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