Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy
Introduction
Cancer chemotherapy is limited by the development of drug resistance in tumors and adverse side effects in patients. The search for novel anti-tumor agents that circumvent these limitations has turned to natural sources, in particular plants used in traditional folk medicines. This approach has already proven successful. Camptothecin from Camptotheca acuminata and paclitaxel from Taxus brevifolia are outstanding examples of natural products as chemotherapeutic agents (Wall and Wani, 1995).
The genus Artemisia L. belongs to the family of Compositae. More than 350 Artemisia species are known, many of which have been used in traditional folk medicines for various applications (cough, blood circulation, diuresis, hypertension, allergy, parasites, etc.). Sesquiterpene lactones, flavonoids, coumarins, acetylenes, and sterols have been isolated from Artemisia species, some of which reveal anti-malarial, anti-viral, anti-tumor, anti-pyretic, anti-coagulant, anti-spasmodic, and other effects (Tan et al., 1998).
Artemisinin, a sesquiterpene lactone from Artemisia annua L. (qinghao, Sweet wormwood) has raised considerable attention in past years. The plant has been used in China for more than two millenia. Its first description dates back to the third century bc. Ge Hong (281–340 ad) recommended tea-brewed leaves to treat fever and chills in his “Handbook of Prescriptions for Emergency Treatment”. The “Compendium of Materia Medica” published by Li Shizen in 1596 cited Ge Hong's prescription. The fact that qinghao tea has withstood the centuries may be taken as a clue for the usefulness and activity of this prescription of traditional Chinese medicine (TCM).
A program for the discovery of new anti-malarial drugs from TCM launched by the Chinese government led in 1972 to the identification of artemisinin (qinghaosu), the active principle of A. annua L. (Klayman, 1985, Butler and Wu, 1992). Today, several tons per year of artemisinin are extracted from A. annua L. plants for pharmaceutical utilization in Asian countries (Haynes, 2001), which points to a preservation issue of wild-growing plants and which necessitates the cultivation in plantations for large scale production. Due to the low solubility of artemisinin in oil and water, several semi-synthetic derivatives have been developed, including artemether, arteether, artesunate, and others (Fig. 1). The attractiveness of the artemisinin class of anti-malarials is due to their activity against multidrug-resistant Plasmodium falciparum and Plasmodium vivax strains (Price et al., 1998). Another salient feature is the lack of severe side effects in malaria patients (Ribeiro and Olliaro, 1998), although neurotoxicity occurs in animals after prolonged treatment with supra-therapeutic doses (Brewer et al., 1994, Kamchonwongpaisan et al., 1997, Gordi and Lepist, 2004).
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Anti-proliferative activity
During the past years, a number of tumor cell lines have been tested for their sensitivity to artemisinin and first generation derivatives (artesunate, artemether, arteether). While artemisinin and its derivatives kill malaria parasites at nanomolar concentrations, they exhibit cytotoxicity towards mammalian cells in the nanomolar to micromolar range (Sun et al., 1992, Woerdenbag et al., 1993, Zheng, 1994; Lai and Singh, 1995; Efferth et al., 1996, Beekman et al., 1997a).
Using a panel of 55
Multidrug resistance
A salient feature of artemisinin and its derivatives is the lack of cross-resistance with other anti-malarials. Drug resistance is a huge problem in malaria treatment worldwide. Artemisinin and its derivatives are valuable for the treatment of otherwise unresponsive, multidrug-resistant malaria parasites (Price et al., 1998). Although Plasmodium strains resistant to artemisinin and its derivatives have been selected in vitro (Walker et al., 2000), resistance to this drug class has not been
Pharmacogenomics
Because the molecular mechanisms of action of artemisinin and its derivatives in tumor cells are largely unknown, we applied pharmacogenomic approaches to explore the molecular determinants of sensitivity and resistance to this drug class. We mined the genome-wide mRNA expression database and correlated the expression data with the IC50 values for artesunate as reported by us (Efferth et al., 2001) and other artemisinin derivatives deposited in the database. This is a hypothesis-generating
Oxidative stress and iron
In malaria parasites, artemisinin acts by a two-step mechanism. It is first activated by intraparasitic heme-iron, which catalyzes the cleavage of the endoperoxide. The Plasmodium trophozoites and schizonts live within red blood cells. Hemoglobin serves as an amino acid source, being taken up by the parasites into food vacuoles where enzymatic degradation takes place (Semenov et al., 1998, Shenai et al., 2000). The release of heme-iron during hemoglobin digestion facilitates the cleavage of the
Toxicity
Neurotoxicity has been reported in safety studies with movement disturbances and neuropathic changes occur in the hindbrain of intramuscularly treated dogs, rats, and monkeys after using extremely high doses or after prolonged exposure (Kamchonwongpaisan et al., 1997). Such effects have not been seen in malaria patients. A recent clinical safety review of 108 clinical studies enrolling 9241 patients provided ample evidence that artemisinins are safe and without serious adverse events or severe
Apoptosis
Since most anti-cancer drugs kill tumor cells by the induction of apoptosis, it is reasonable to assume that the same is true for artemisinin and its derivatives. There are two main pathways that trigger apoptosis (Schimmer et al., 2001, Fulda and Debatin, 2003, Green and Kroemer, 2004). Both the extrinsic and the intrinsic pathway of apoptosis are regulated by the tumor suppressor gene p53 (Haupt et al., 2003). Members of the tumor necrosis factor family activate the receptor-mediated
Angiogenesis
In the angiogenic process, the formation of new blood vessels from pre-existing ones is essential for the supply of tumors with oxygen and nutrients and for the spread of metastatic cells throughout the body (Folkman, 1992). Angiogenesis is promoted by numerous factors including cytokines, VEGF, bFGF, PDGF, etc. and negatively regulated by angiostatin, endostatin, thrombospondin, TIMP, and others. These factors, which are produced in tumor cells as well as in surrounding stromal cells, act in a
Perspectives
Considerable progress has been made during the past years towards understanding the molecular modes of action of artemisinin and its derivatives against tumor cells. Diverse lines of research show that the cellular response to artemisinin and its derivatives is multi-factorial in nature (Fig. 5). This may be beneficial in treating otherwise drug-resistant tumors and may explain why the development of artemisinin resistance has not yet been encountered in cancer cell lines or malaria patients.
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