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.

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 mononuclear 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 6-24h. We further found NF-kappaB nuclear translocation were prevented by CDA-II treatment, which therefore inactivated NF-kappaB 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-kappaB 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-kappaB, involving in Bcl-2 family and XIAP, which has no cytotoxicity on normal cells.

• Authors: Jian Huang, Min Yang, Hui Liu, Jie Jin
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 47 Issue 1 Pg. 40-9 (Jan 2009) ISSN: 1873-6351 [Electronic] England
• PMID: 18761050 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BAX protein, human
• COL11A2 protein, human
• Collagen Type XI
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• NF-kappa B
• Peptides
• Phenylacetates
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• cell differentiation agent II
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Bone Marrow Cells (drug effects)
• Caspases (metabolism)
• Cell Line, Tumor
• Collagen Type XI (metabolism)
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• Granulocyte Precursor Cells (drug effects)
• Humans
• Leukemia, Myeloid, Acute
• Leukocytes, Mononuclear (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, SCID
• Myeloid Cell Leukemia Sequence 1 Protein
• NF-kappa B (antagonists & inhibitors)
• Neoplasms, Experimental (drug therapy)
• Peptides (pharmacology)
• Phenylacetates (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• bcl-2-Associated X Protein (metabolism)