Bao-Ning Su

The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo

Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections. In the National Cancer Institute cell line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B cells. We investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL cells, silvestrol LC(50) (concentration lethal to 50%) is 6.9 nM at 72 hours. At this concentration, there is no difference in sensitivity of cells from patients with or without the del(17p13.1) abnormality. In isolated cells and whole blood, silvestrol is more cytotoxic toward B cells than T cells. Silvestrol causes early reduction in Mcl-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization. In vivo, silvestrol causes significant B-cell reduction in Emu-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (SCID) mice without discernible toxicity. These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias.

Induction of the Phase II Enzyme, Quinone Reductase, by Withanolides and Norwithanolides from Solanaceous Species

The induction of the phase II drug-metabolizing enzyme, NAD(P)H:quinone reductase (QR), using Hepa 1c1c7 hepatoma cells, is currently used as a key member of a panel of in vitro bioassays in our program directed towards the discovery of new plant- derived cancer chemopreventive agents. Among a group of natural products, which have been studied as QR inducers are the withanolides, which constitutes about 400 C 28 ergostane-type steroids found mainly in approximately 10 genera of the plant family Solanaceae. New withanolides have been isolated and characterized in our recent work on Physalis philadelphica (tomatillo), which is used as a vegetable and condiment in Mexican and Central American cuisine. A further study on Deprea subtriflora has led to the discovery of a new class of C-18 norwithanolides with only 27 carbons in their skeleton. Preliminary structure-activity relationships have been determined for the in vitro induction of QR by members of the withanolide and norwithanolide classes.

Potential cancer chemopreventive agents from Arbutus unedo

A phytochemical study of the petroleum ether and ethyl acetate extracts of the entire plant of Arbutus unedo led to the isolation of a new sterol, 7β-hydroxystigmast-4-en-3-one (1), and nine known compounds of the flavan, steroid, and terpenoid types. The structure of 1 was determined by spectroscopic data interpretation in combination with molecular modeling calculations. The absolute stereochemistry of C-7 was assigned as S for compound 1 based on the obtained CD spectral data. Activity in the JB6 cell transformation assay was found for pomolic acid 3-acetate (4). All isolates obtained were evaluated in a cyclooxygenase-2 (COX-2) inhibition assay.

Compounds obtained from Sida acuta with the potential to induce quinone reductase and to inhibit 7,12-dimethylbenz-[ a]anthracene-induced preneoplastic lesions in a mouse mammary organ culture model

Activity-guided fractionation of the EtOAc-soluble extract of the whole plants ofSida acuta using a bioassay based on the induction of quinone reductase (QR) in cultured Hepa 1c1c7 mouse hepatoma cells, led to the isolation of ten active compounds of previously known structure, quindolinone (1), cryptolepinone (2), 11-methoxyquindoline (3),N-trans-feruloyltyramine (4), vomifoliol (5), loliolide (6), 4-ketopinoresinol (7), scopoletin (8), evofolin-A (9), and evofolin B (10), along with five inactive compounds of known structure, ferulic acid, sinapic acid, syringic acid, (±)-syringaresinol, and vanillic acid. These isolates were identified by physical and spectral data measurement. A new derivative of quindolinone, 5,10-dimethylquindolin-11-one (1a) was synthesized and characterized spectroscopically. Of the active substances, compounds1-3 and1a exhibited the most potent QR activity, with observed CD (concentration required to double induction) values ranging from 0.01 to 0.12 μg/mL. Six compounds were then evaluated in a mouse mammary organ culture assay, with cryptolepinone (2),N-trans-fer-uloyltyramine (4), and 5,10-dimethylquindolin-11-one (1a) found to exhibit 83.3, 75.0, and 66.7% inhibition of 7,12-dimethylbenz[a]anthracene-induced preneoplastic lesions, respectively, at a dose of 10 μg/mL.