title: 2',5,7-Trihydroxy-4',5'-(2,2-dimethylchromeno)-8-(3-hydroxy-3-methylbutyl) flavanone purified from Cudrania tricuspidata induces apoptotic cell death of human leukemia U937 cells.
abstract: Cellular DNA topoisomerase I is an important target in cancer chemotherapy. A chloroform extract of the root barks of Cudrania tricuspidata showed an inhibitory effect on mammalian DNA topoisomerase I. The topoisomerase I inhibitory compound was purified and identified as 2',5,7-trihydroxy-4',5'-(2,2-dimethylchromeno)-8-(3-hydroxy-3-methylbutyl) flavanone. The compound, temporarily designated as PKH-3, was shown to inhibit the activity of topoisomerase I with IC50 about 1.0 mM. Concentration of 10 microM PKH-3 caused 50% growth inhibition of human cancer cell U937. PKH-3-induced cell death was characterized with the cleavage of poly(ADP-ribose) polymerase (PARP) and pro-caspase 3. Furthermore, PKH-3 induced the fragmentation of DNA into multiples of 180 b.p. (an apoptotic DNA ladder), indicating that the inhibitor triggered apoptosis. This induction of apoptosis by PKH-3 was also confirmed using flow cytometry analysis. Taken together, these results suggest that PKH-3 may function by inhibiting oncogenic disease, at least in part, through the inhibition of topoisomerase I activity.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Yoon-Hwa
authors.initials: YH
authors.lastname: Rho
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Yoon
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kang
authors.forename: Byong-Won
authors.initials: BW
authors.lastname: Lee
authors.forename: Ki-Hun
authors.initials: KH
authors.lastname: Park
authors.forename: Young-Seuk
authors.initials: YS
authors.lastname: Bae
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D047309:Flavones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D013058:Mass Spectrometry; D029586:Moraceae / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D018517:Plant Roots / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D020298:U937 Cells
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D047309:Flavones; D004264:DNA Topoisomerases, Type I