title: Discovery of novel inducers of cellular differentiation using HL-60 promyelocytic cells.
abstract: Non-physiological inducers of terminal differentiation have been used as novel therapies for the prevention and therapy of cancer. We have used cultured HL-60 promyelocytic cells to monitor differentiation, proliferation and cell death events as induced by a large set of extracts derived from plants. Screening of more than 1400 extracts led to the discovery of 34 with potent activity (ED50 <8 mg/ml). Bioassay-guided fractionation led to the isolation of zapotin and 2',5,6-trimethoxyflavone as active principles from Casimiroa edulis, dibenzyltrisulfide and 2-[(phenylmethyl)dithio]ethanol as active principles from Petiveria alliacea, and desmethylrocaglamide from Aglaia ponapensis. Zapotin demonstrated the most favorable biological profile in that induction of differentiation correlated with proliferation arrest, and a lack of cytotoxicity. We conclude that the HL-60 cell model is a useful system for the discovery of novel pharmacophores with potential to suppress the process of carcinogenesis, and that flavonoids may be especially useful in this capacity.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mata-Greenwood
authors.forename: A
authors.initials: A
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Westenburg
authors.forename: B
authors.initials: B
authors.lastname: Cui
authors.forename: R G
authors.initials: RG
authors.lastname: Mehta
authors.forename: A D
authors.initials: AD
authors.lastname: Kinghorn
authors.forename: J M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001681:Biological Assay; D002273:Carcinogens; D016923:Cell Death; D002454:Cell Differentiation; D002455:Cell Division; D004950:Esterases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007202:Indicators and Reagents / Q000494:pharmacology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D009580:Nitroblue Tetrazolium / Q000494:pharmacology; D009924:Organ Culture Techniques; D010936:Plant Extracts / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D007202:Indicators and Reagents; D010936:Plant Extracts; D009580:Nitroblue Tetrazolium; D015127:9,10-Dimethyl-1,2-benzanthracene; D004950:Esterases