lignans and Leukemia--T-Cell

Adult T-cell leukemia is an aggressive hematological malignancy with a poor clinical prognosis, and a rapid resistance to chemotherapy is rapid.. Cytotoxicity assay-directed fractionation identified a novel lignan-related agent, 4-methoxy-9-(3,4,5-trimethoxyphenyl)-8, 9 - dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5H)-one (4-MTDND) from the Jamaican plant Hyptis verticillata jacq, and its effects on apoptosis, cell cycle and drug resistance were elucidated.. The novel agent, 4-MTDND, exhibited cytotoxicity against myriad cancer types, with a wide therapeutic index of 30- to 40-fold, promoted G(2)/M arrest and up-regulated expression of pro-apoptotic proteins p53 and BAX, as well as enhanced activation of caspase-3, caspase-9 and poly (ADP ribose) polymerase, consistent with apoptosis induction. Multidrug-resistant cancer cells were as susceptible to 4-MTDND as their non-resistant control counterparts, with 4-MTDND having greater efficacy compared to standard chemotherapy agents etoposide and mitoxantrone.. The novel cytotoxic agent 4-MTDND induces G(2)/M arrest and apoptosis in cancer cells possibly due to direct DNA damage or interference with topoisomerase II.

Topics: Antineoplastic Agents; Apoptosis; Cytotoxins; Dioxolanes; DNA Damage; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Gene Expression Regulation, Neoplastic; Human T-lymphotropic virus 1; Humans; Hyptis; Leukemia, T-Cell; Lignans; Mitoxantrone; Plant Extracts; Poly(ADP-ribose) Polymerases; Topoisomerase Inhibitors

Anti leukemic-cell efficacy of 28 naturally occurring and synthetic flavonoids and 11 naturally occurring lignans on human promyelocytic leukemic cell line HL-60 were examined using MTT assay methods. Differences between anti cell-proliferative activity and cytotoxicity of these compounds were compared with those of 4 clinical anti-cancer agents. Eight of the 28 flavonoids and 4 of the 11 lignans showed considerable suppressive effects on HL-60 cell growth with IC50s ranging from 10-940 ng/ml. Among these compounds, genistein, honokiol, machilin A, matairesinol, and arctigenin had the strongest effects with IC50s less than 100 ng/ml, which were almost equivalent to the effects of current anti-cancer agents. The flavonoid genistein and the lignans, however, showed little or no cytotoxicity against HL-60 cells as assessed by dye exclusion tests (LC50s > 2,900 ng/ml), whereas the regular anti-cancer agents had potent cytotoxicity. All of the flavonoids and lignans, except for machilin A and arctigenin, were less effective against growth of human T lymphocytic leukemia cell line MOLT-4. In addition, the flavonoid and the lignans showed little or no inhibiting activity on mitogen-induced blastogenesis of human peripheral-blood lymphocytes. The lignans and genistein were strongly suppressive against incorporations of [3H]thymidine, [3H]uridine, and [3H]leucine into HL-60 cells. These results showed that some of the naturally occurring flavonoids and lignans inhibited HL-60 cell growth with a non-toxic mechanism, possibly via cessation of DNA, RNA, and/or protein synthesis of the leukemic cells.

Topics: Antineoplastic Agents; Cell Division; Drug Screening Assays, Antitumor; Flavonoids; Humans; Leucine; Leukemia, Promyelocytic, Acute; Leukemia, T-Cell; Lignans; Lymphocyte Activation; Lymphocytes; Tetrazolium Salts; Thiazoles; Thymidine; Tumor Cells, Cultured; Uridine