No abstract

A profound cytotoxic action of the antimalarial, artesunate (ART), was identified against 55 cancer cell lines of the U.S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC 50 values) for ART correlated significantly to the cell doubling times (P ϭ 0.00132) and the portion of cells in the G 0 /G 1 (P ϭ 0.02244) or S cell cycle phases (P ϭ 0.03567). We selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data base. These genes belong to different biological categories (drug resistance genes, DNA damage response and repair genes, oncogenes and tumor suppressor genes, apoptosis-regulating genes, proliferation-associated genes, and cytokines and cytokine-associated genes). The constitutive expression of 54 of 465 (ϭ12%) genes correlated significantly to the IC 50 values for ART. Hierarchical cluster analysis of these 12 genes allowed the differentiation of clusters with ART-sensitive or ART-resistant cell lines (P ϭ 0.00017). For exemplary validation, cell lines transduced with 3 of the 12 genes were used to prove a causative relationship. The cDNAs for a deletion-mutated epidermal growth factor receptor (EGFR) and for ␥-glutamylcysteine synthetase increased resistance to ART. The conditional expression of the CDC25A gene using a tetracycline repressor expression vector increased sensitivity toward ART. Multidrug-resistant cells differentially expressing the MDR1, MRP1, or BCRP genes were not cross-resistant to ART. ART acts via p53-dependent andindependent pathways in isogenic p53ϩ/ϩ p21 WAF1/CIP1 ϩ/ϩ, p53Ϫ/Ϫ p21 WAF1/CIP1 ϩ/ϩ, and p53ϩ/ϩ p21 WAF1/CIP1

Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicine was triggered in the 1990s, by artemisinin-type sesquiterpene lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis. Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature.

No abstract

Drugs derived from natural resources represent a significant segment of the pharmaceutical market as compared to randomly synthesized compounds. It is a goal of drug development programs to design selective ligands that act on single disease targets to obtain highly effective and safe drugs with low side effects. Although this strategy was successful for many new therapies, there is a marked decline in the number of new drugs introduced into clinical practice over the past decades. One reason for this failure may be due to the fact that the pathogenesis of many diseases is rather multi-factorial in nature and not due to a single cause. Phytotherapy, whose therapeutic efficacy is based on the combined action of a mixture of constituents, offers new treatment opportunities. Because of their biological defence function, plant secondary metabolites act by targeting and disrupting the cell membrane, by binding and inhibiting specific proteins or they adhere to or intercalate into RNA or DNA. Phytotherapeutics may exhibit pharmacological effects by the synergistic or antagonistic interaction of many phytochemicals. Mechanistic reasons for interactions are bioavailability, interference with cellular transport processes, activation of pro-drugs or deactivation of active compounds to inactive metabolites, action of synergistic partners at different points of the same signalling cascade (multi-target effects) or inhibition of binding to target proteins. "-Omics" technologies and systems biology may facilitate unravelling synergistic effects of herbal mixtures.

No abstract

In the present study, the antimicrobial activity of the essential oils from clove (Syzygium aromaticum (L.) Merr. et Perry) and rosemary (Rosmarinus officinalis L.) was tested alone and in combination. The compositions of the oils were analysed by GC/MS. Minimum inhibitory concentrations (MIC) against three Gram-positive bacteria, three Gram-negative bacteria and two fungi were determined for the essential oils and their mixtures. Furthermore, time-kill dynamic processes of clove and rosemary essential oils against Staphylococcus epidermidis, Escherichia coli and Candida albicans were tested. Both essential oils possessed significant antimicrobial effects against all microorganisms tested. The MICs of clove oil ranged from 0.062% to 0.500% (v/v), while the MICs of rosemary oil ranged from 0.125% to 1.000% (v/v). The antimicrobial activity of combinations of the two essential oils indicated their additive, synergistic or antagonistic effects against individual microorganism tests. The time-kill curves of clove and rosemary essential oils towards three strains showed clearly bactericidal and fungicidal processes of (1)/(2) x MIC, MIC, MBC and 2 x MIC.

Secondary metabolites from plants can serve as defense against herbivores, microbes, viruses or competing plants. Many compounds from medicinal plants have pharmacological activities and thus may be a source for novel anti-tumor agents. We have analyzed natural products from traditional Chinese medicine during the past decade and focused our interest on the compound artemisinin from Artemisia annua L. (qinghao, sweet wormwood) and its derivatives. In addition to their anti-malarial properties, artemisinins are cytotoxic for cancer cells. The present review focuses on the mechanisms of action of artemisinins in cancer cells relating to: 1. anti-proliferative and anti-angiogenic effects, 2. induction of apoptosis, 3. oxidative stress, 4. oncogenes and tumor suppressor genes, and 5. multidrug resistance. Data on putative target molecules of artemisinins are presented and discussed, e.g. the translationally controlled tumor protein (TCTP). Emphasis is given to pharmacogenomic approaches to analyze the pleiotropic nature of mechanisms of artemisinins in cancer cells.