Plumbagin and shikonin, plant metabolites which have naphthoquinone structures, induced mammalian topoisomerase II-mediated DNA cleavage in vitro. Treatment of a reaction mixture containing these naphthoquinones and topoisomerase II at an elevated temperature (65°C) resulted in a great reduction in DNA cleavage, suggesting that the mechanism of the topoisomerase II-mediated DNA cleavage induced by these naphthoquinones is through formation of a cleavable complex, as seen with antitumor agents such as 4'-(9-acridinylamino)methanesulfon-m-anisidide and demethylepipodophyllotoxin ethylidene-13-glucoside.Lawson and lapacol, which are structurally related plant metabolites with naphthoquinone moieties, could not induce topoisomerase U-mediated DNA cleavage. Plumbagin and shikonin induced a similar DNA cleavage pattern with topoisomerase II which was different from the cleavage patterns induced with other known topoisomerase II-active drugs. A DNA-unwinding assay with T4 DNA ligase showed that shikonin, lawson, and lapacol did not intercalate into DNA, while plumbagin and 2-methyl-1,4-naphthoquinone intercalate into DNA, but to a lower degree than 4'-(9-acridinylamino)methanesulfon-m-anisidide does.DNA topoisomerases are a class of enzymes that alter DNA conformation through a concerted breaking and rejoining of the DNA molecule, thereby controlling the topological state of DNA. They are reported to be involved in many important processes of DNA metabolism including replication, transcription, recombination, and chromosome segregation (38). In addition, topoisomerases have been potential targets for chemotherapy. Bacterial topoisomerase II (DNA gyrase) is well known as the primary target of quinolone antibacterial agents. Mammalian topoisomerase II has also been identified as the primary cellular target for a number of clinically important antitumor agents which include intercalating agents [e.g., 4'-(9-acridinylamino)methanesulfon-manisidide {m-AMSA}, adriamycin, and ellipticine] as well as nonintercalating agents (e.g., VP16 and VM26 [epipodophyllotoxin]) (6,29,34,35). All of these drugs trap topoisomerase II in an intermediary conformation with DNA, termed the "cleavable complex," which can be detected as DNA double-strand breaks upon treatment of the complex with protein denaturants. Structure-activity studies of a large number of acridine derivatives, epipodophyllotoxin congeners, and antitumor quinolones have shown a strong correlation between antitumor activity and the ability to induce the cleavable complex (23,31,39). In addition, there is now good evidence that mammalian topoisomerase I is the cellular target of camptothecin, an alkaloid with antitumor activity which was isolated from the Chinese tree Camptotheca acuminata. Camptothecin derivatives have shown promising activities in clinical studies (12,16 purified mammalian topoisomerases. We found that the plant naphthoquinones plumbagin and shikonin are potent inducers of the cleavable complex formation with topoisomerase II in vitro.In this report, we de...

Peanut skin (Arachis hypogaea L., Fabaceae) is an abundant source for polyphenols, such as proanthocyanidin oligomers. To determine whether proanthocyanidin has beneficial effects on skin, we tested for inhibitory activity of proanthocyanidins isolated from peanut skin on inflammatory cytokine production and melanin synthesis in cultured cell lines. Administration of peanut skin extract (PSE, 200 µg/mL) decreased melanogenesis in cultured human melanoma HMV-II co-stimulated with phorbol-12-myristate-13-acetate. It also decreased production of inflammatory cytokines (PSE at 100 µg/mL), tumor necrosis factor-α and interleukin-6, in cultured human monocytic THP-1 cells in response to lipopolysaccharide. We isolated ten known proanthocyanidins and one new proanthocyanidin trimer from the PSE. The structure of the new compound (5) was determined by 1D- and 2D-NMR and mass spectrometry analyses, and was determined as epicatechin-(2β→O→7,4β→6)-epicatechin-(4β→6)-epicatechin. The other known proanthocyanidins were identified as proanthocyanidin monomers (1), dimers (6-9), trimers (3-5) and tetramers (2, 10, 11). They showed suppressive activities against melanogenesis and cytokine production at concentrations ranging from 0.1-10 µg/mL. Among the tested compounds, suppressive activities of proanthocyanidin dimers or trimers in two assay systems were stronger than those obtained with monomer or tetramers. These data indicate that proanthocyanidin oligomers from peanut skin have the potential to reduce dermatological conditions such as inflammation and melanogenesis.

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