Capsicodendrin from <i>Cinnamosma fragrans</i> Exhibits Antiproliferative and Cytotoxic Activity in Human Leukemia Cells: Modulation by Glutathione

Capsicodendrin (CPCD, <b>1</b>), an epimeric mixture of a dimeric drimane-type sesquiterpene, is one of the major compounds present in the three endemic species of Madagascan traditional chemopreventive plants: <i>Cinnamosma</i> species (<i>C. fragrans, C. macrocarpa</i>, and <i>C. madagascariensis</i>). Despite the popular use of <i>Cinnamosma</i> in Madagascan traditional medicine and the reported antiproliferative properties of CPCD, elucidation of its mechanism(s) of action is still to be accomplished. In the present study, CPCD at low micromolar concentrations was cytotoxic and induced apoptosis in human myeloid leukemia cells in a time- and concentration-dependent manner. The activity of CPCD in HL-60 and K562 cells was modulated by glutathione (GSH), since depletion of this intracellular thiol-based antioxidant with buthionine sulfoximine resulted in significantly (<i>p</i> < 0.05) greater potency in antiproliferation assays. GSH depletion also significantly potentiated the cytotoxic activity in CPCD-treated human HL-60 cells. Single-cell gel electrophoresis (Comet) assays revealed that GSH depletion in HL-60 cells enhanced the formation of DNA strand breaks in the presence of CPCD. Although CPCD does not contain an obvious Michael acceptor in its structure, ¹H NMR analyses indicated that cinnamodial (<b>2</b>), a monomer of CPCD, was formed within a few hours when dissolved in DMSO-<i>d</i>₆ and interacts with GSH to form a covalent bond via Michael addition at the C-7 carbon. Together the results strongly suggest that <b>2</b> is responsible for the DNA-damaging, pro-apoptotic, and cytotoxic effects of CPCD and that depletion of GSH enhances overall activity by diminishing covalent interaction between GSH and this 2-alkenal decomposition product of CPCD

Potent Cytotoxic Arylnaphthalene Lignan Lactones from <i>Phyllanthus poilanei</i>

Two new (<b>1</b> and <b>2</b>) and four known arylnaphthalene lignan lactones (<b>3</b>–<b>6</b>) were isolated from different plant parts of <i>Phyllanthus poilanei</i> collected in Vietnam, with two further known analogues (<b>7</b> and <b>8</b>) being prepared from phyllanthusmin C (<b>4</b>). The structures of the new compounds were determined by interpretation of their spectroscopic data and by chemical methods, and the structure of phyllanthusmin D (<b>1</b>) was confirmed by single-crystal X-ray diffraction analysis. Several of these arylnaphthalene lignan lactones were cytotoxic toward HT-29 human colon cancer cells, with compounds <b>1</b> and 7-<i>O</i>-[(2,3,4-tri-<i>O</i>-acetyl)-α-l-arabinopyranosyl)]­diphyllin (<b>7</b>) found to be the most potent, exhibiting IC₅₀ values of 170 and 110 nM, respectively. Compound <b>1</b> showed activity when tested in an in vivo hollow fiber assay using HT-29 cells implanted in immunodeficient NCr <i>nu</i>/<i>nu</i> mice. Mechanistic studies showed that this compound mediated its cytotoxic effects by inducing tumor cell apoptosis through activation of caspase-3, but it did not inhibit DNA topoisomerase IIα activity