ABSTRACT
Three new flavonoids, (2R,3R)-3,5-dihydroxy-7-methoxyflavanone 3-(2-methyl)butyrate (1), (7''R)-8-[1-(4'-hydroxy-3'-methoxyphenyl)prop-2-en-1-yl]chrysin (2), and (7''R)-8-[1-(4'-hydroxy-3'-methoxyphenyl)prop-2-en-1-yl]galangin (3), together with 41 known compounds (4-44) were isolated from a methanolic extract of Mexican propolis. Compounds 2 and 3 are unique natural flavones containing a 1-phenylallyl moiety. The in vitro preferential cytotoxicity of all the isolates was evaluated against a PANC-1 human pancreatic cell line. Compound 3 displayed the most potent preferential cytotoxicity (PC(50) 4.6 microM) in the nutrient-deprived medium (NDM) and triggered apoptosis-like morphological changes in PANC-1 cells.
Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Flavonoids/isolation & purification , Flavonoids/pharmacology , Propolis/chemistry , Propolis/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis/physiology , Bees , Drug Screening Assays, Antitumor , Flavonoids/chemistry , Humans , Mexico , Molecular Structure , Pancreatic Neoplasms/drug therapy , StereoisomerismABSTRACT
Human pancreatic cancer cells such as PANC-1 are known to exhibit marked tolerance to nutrition starvation that enables them to survive for prolonged period of time even under extremely nutrient-deprived conditions. Thus, elimination of this tolerance to nutrition starvation is regarded as a novel approach in anticancer drug development. In this study, the MeOH soluble extract of Brazilian red propolis was found to kill 100% PANC-1 cells preferentially in the nutrient-deprived condition at the concentration of 10 microg/mL. Further phytochemical investigation led to the isolation of 43 compounds including three new compounds, (6aS,11aS)-6a-ethoxymedicarpan (1), 2-(2',4'-dihydroxyphenyl)-3-methyl-6-methoxybenzofuran (2), and 2,6-dihydroxy-2-[(4-hydroxyphenyl)methyl]-3-benzofuranone (3). Among them, (6aR,11aR)-3,8-dihydroxy-9-methoxypterocarpan (21, DMPC) displayed the most potent 100% preferential cytotoxicity (PC(100)) at the concentration of 12.5 microM. Further study on the mode of cell death induced by DMPC against PANC-1 cells indicated that killing process was not accompanied by DNA fragmentation, rather through a nonapoptotic pathway accompanied by necrotic-type morphological changes.