Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy.
In addition to their well-known anti-malarial activity, artemisinin and its derivatives (1,2,4-trioxanes) possess potent activity against tumor cells in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. These genes are from classes with different biological function; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Anti-oxidant stress genes (thioredoxin, catalase, gamma-glutamyl-cysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines over-expressing genes that confer resistance to established anti-tumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that this drug has a different target and is not subject to multidrug resistance. The Plasmodium translationally controlled tumor protein (TCTP) represents a known target protein of artemisinin and its derivatives in the malaria parasite. The microarray-based mRNA expression of human TCTP correlated with sensitivity to artesunate in tumor cells, suggesting that human TCTP contributes to response of tumor cells to the drug. The multi-factorial nature of cellular response to artemisinin and its derivatives may be beneficial to treat otherwise drug-resistant tumors and may explain why resistance development has not been observed in either cancer or malaria.
Efferth
Thomas
T
German Cancer Research Center, M070, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. thomas.efferth@web.de
D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000378:metabolism / Q000627:therapeutic use*; D016000:Cluster Analysis; D018432:Drug Resistance, Multiple / Q000235:genetics*; D006571:Heterocyclic Compounds / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D010597:Pharmacogenetics; D012717:Sesquiterpenes / Q000378:metabolism / Q000627:therapeutic use*; D000090324:Tumor Protein, Translationally-Controlled 1
C503429:1,2,4-trioxane; D000962:Antimalarials; D037621:Artemisinins; D006571:Heterocyclic Compounds; D012717:Sesquiterpenes; C000715647:TPT1 protein, human; D000090324:Tumor Protein, Translationally-Controlled 1; C031327:artemisinin