title: Characterization of proapoptotic compounds from the bark of Garcinia oblongifolia.
abstract: Twenty compounds from Garcinia oblongifolia were screened for proapoptotic activity using FRET-based HeLa-C3 sensor cells. Among them, oblongifolins F and G (1 and 2), 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran[7,6-b]xanthone (3), nigrolineaxanthone T (4), and garcicowin B (5) showed significant proapoptotic activity at a concentration of 10 μM. Bioassessments were then performed to evaluate the potential of these compounds for therapeutic application. All five compounds showed significant cytotoxicity and caspase-3-activating ability in cervical cancer HeLa cells, with compounds 1 and 2 having the highest potencies. All five compounds specifically induced caspase-dependent apoptosis, which could be prevented by the pan-caspase inhibitor zVAD-fmk. In particular, 3 induced apoptosis through mitotic arrest. Compounds 1-5 displayed similar IC50 values (3.9-16.5 μM) against the three cancer cell lines HeLa, MDA-MB-435, and HepG2. In addition, compounds 1, 2, and 4 exhibited similar and potent IC50 values (2.4-5.1 μM) against several breast and colon cancer cell lines, including those overexpressing either HER2 or P-glycoprotein. HER2 and P-glycoprotein are known factors that confer resistance to anticancer drugs in cancer cells. This is the first study on the cytotoxicity, caspase-3-activing ability, and specificity of proapoptotic compounds isolated from G. oblongifolia in HeLa cells. The potential application of these compounds against HER2- or P-glycoprotein-overexpressing cancer cells was investigated.
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Hong Kong University of Science and Technology , Clear Water Bay, Hong Kong.
authors.forename: Chao
authors.initials: C
authors.lastname: Feng
authors.forename: Sheng-Xiong
authors.initials: SX
authors.lastname: Huang
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Gao
authors.forename: Hong-Xi
authors.initials: HX
authors.lastname: Xu
authors.forename: Kathy Qian
authors.initials: KQ
authors.lastname: Luo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D061945:Caspase Inhibitors; D005260:Female; D029760:Garcinia / Q000737:chemistry*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D024301:Plant Bark / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D044004:Xanthones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000590:Amino Acid Chloromethyl Ketones; D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D061945:Caspase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D044004:Xanthones; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone