Artemisinin – Encyclopedia of Cancer
Henry Laia*, Narendra P. Singha and Tomikazu Sasakib
aDepartments of Bioengineering, University of Washington, Seattle, WA, USA bDepartment of Chemistry, University of Washington, Seattle, WA, USA
Synonyms
Antimalarial; Artemisinin; Cancer cell cytotoxicity; Free radical; Selective effect Definition
Artemisinin, a natural product (Fig. 1) isolated from the sweet wormwood Artemisia annua L, is a sesquiterpene lactone. Artemisinin has molecular formula of C15H22O5 (MW = 282.34). The structure of artemisinin contains fused 6- and 7-membered rings with a peroxide bridge (endoperoxide). Pure artemisinin is a white and crystalline powder that melts at 152–157 C. Artemisinin is soluble in organic solvents but almost insoluble in water.
Characteristics
Biological Activity
Artemisinin is being used in humans as a potent antimalarial. Its effectiveness on malaria is due to its endoperoxide moiety (R1–O–O–R2) that reacts with heme, which is abundant in malaria parasites, leading to the formation of carbon-based free radicals which in turn cause death of the parasite. Artemisinin is also being developed into an anticancer therapeutic agent (Lai et al. 2013). The rationale is that cancer cells, like the malaria parasites, contain high concentration of ▶ intracellular free iron. Cell death also results from the formation of free radicals by the artemisinin-iron reaction. This property of artemisinin enables it to be effective against many different types of cancer cells. The advantage of artemisinin as an anticancer agent is not only in its potency as a toxic agent to cancer cells but also in its selectivity in killing cancer cells and low toxicity to normal cells, since normal cells contain significantly less free iron. However, artemisinin compounds have multiple mechanisms of action on cancer. They have also been shown to have antiproliferation, anti-angiogenic, ▶anti-metastasis, and ▶anti-inflammatory properties. All of these are beneficial to cancer treatment and, probably, prevention.
Artemisinin Monomers
In addition to the parent compound, a number of synthetic derivatives of artemisinin have been reported. The common artemisinin monomers (artemisinin, dihydroartemisinin, artesunate, and artemether (Fig. 1)) have been tested on many different types of cancer cells. Results indicate that they are toxic to cancer cells with IC50s in the 10–20 mM range. Dihydroartemisinin, artesunate, and artemether are generally more potent than artemisinin when tested in vitro. Cancer cells and models studied include brain cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, hepatoma, leukemia, lung cancer, lymphoma, melanoma, myeloma, nasopharyngeal cancer, oral cancer, osteosarcoma, ovarian
*Email: [email protected]
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Encyclopedia of Cancer
DOI 10.1007/978-3-642-27841-9_7201-1 # Springer-Verlag Berlin Heidelberg 2014
Fig.1 Molecularstructuresofseveralcommonartemisininmonomers
cancer, pancreatic cancer, papillomavirus-expressed epithelial cells, prostate cancer, skin cancer, and thyroid cancer. According to NCI’s screening data, leukemia cells are the most sensitive to artemisinin and its derivatives. In general, artemisinin compounds have been shown to be more toxic toward cancer cells than their corresponding normal cells. Most cancer cells have high rates of iron uptake to support their uncontrolled growth and may become more sensitive to artemisinin. This represents a major advantage of artemisinin when used as a chemotherapeutic agent.
Mechanism of Action
Artemisinins affect many different cellular pathways that are involved in cellular development, prolifer- ation, and apoptosis. Thus, both cell death and growth inhibition occur. However, the site of action is not clear. There are reports of involvement of mitochondria and its apoptotic pathway, extramitochondrial mode of action, involvements of iron/heme, and reactive oxidative species. Two processes that have repeatedly been reported to be affected by artemisinins are inhibition of nuclear factor kappaB (NF-kB) and decrease in vascular endothelial growth factor (VEGF) activities. Artemisinin derivatives induce programmed cell death of cancer cells by activating the intrinsic or the cytochrome c-mediated pathway for apoptosis. Effects on other cellular pathways have also been reported including NOXA, mitogen- activated protein kinase (MAPK), hypoxia-inducible factor 1a (HIF-1a), Wnt/b-catenin, survivin, COX, c-MYC oncoprotein, epidermal growth factor (EGF), and tumor necrosis factor-a (TNF-a). These molecular effects could explain the apoptotic, anti-angiogenic, anti-inflammatory, anti-metastasis, and cell cycle inhibition effects of artemisinin compounds.
Other Artemisinin-Like Compounds
In addition to the basic monomeric compounds, other artemisinin-like compounds have been developed. These other compounds include artemisone, tehranolide, artemisinin-glycolipid, deoxoartemisinin, azaartemisinin derivatives, artemisinin dimers and trimers, tetraoxanes, and artemisinin tagged to iron delivery proteins such as transferrin. Other preparations, such as lipid nanoparticle formulations, have also been investigated. Artemisinin dimers (Fig. 2) are the most well studied and have been tested in many different cancer cell lines and found to be effective in either retarding their growth or causing cell death (apoptosis). They are also the most promising candidate for development into cancer therapeutic agents. In general, cancer cell cytotoxicity of dimers is more potent than that of the monomers. The increase in potency varies from 10- to 200-fold. Artemisinin dimers have also been shown to be as or even more potent than some chemotherapeutic agents, such as doxorubicin, and much less toxic to normal cells than cancer cells. However, artemisinin dimers cannot be considered as a single group of compounds with similar general properties. The arrangement of atoms in the molecule, the chemical characteristics of the linkers, and the in vivo pharmacokinetics of a dimer can determine the cytotoxic effectiveness and action of the compound on cancer cells.
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Encyclopedia of Cancer
DOI 10.1007/978-3-642-27841-9_7201-1 # Springer-Verlag Berlin Heidelberg 2014
Fig. 2 Molecular structures of two artemisinin dimers (Dimer-Sal and Dimer-OH) and the monomer dihydroartemisinin (DHA)
Synergism with Other Chemotherapeutic Agents
Combination of artemisinin compounds with traditional chemotherapeutic agents may achieve a syner- gistic effect with fewer side effects. Synergism has been reported between artesunate with fotemustine and dacarbazine on human uveal melanoma; artesunate and epidermal growth factor receptor tyrosine kinase inhibitor on glioblastoma multiforme cells; artesunate and vinorelbine and cisplatin on human non-small cell lung cancer; dihydroartemisinin and temozolomide on rat C6 glioma cells; artemisinin and dihydroar- temisinin with gemcitabine on hepatoma xenograft in mice; dihydroartemisinin and carboplatin on ovarian cancer cells in vitro and in vivo; dihydroartemisinin and gemcitabine on pancreatic cancer xenograft in mice; dihydroartemisinin with cisplatin and cyclophosphamide on lung cancer xenografts in mice; artesunate with lenalidomide on A549 lung cancer cells and MCF7 breast cancer cells (but not on HCT116 colon cancer cells); artemisone with gemcitabine, oxaliplatin, and thalidomide on human colon and breast cancer cells; and artesunate and the anti-CD20 antibody rituximab.
Effective on Drug-Resistant Cancer Cells
Artemisinin compounds have been shown to be toxic toward various ▶ multiple drug-resistant cancer cell lines. Artemisinin has been shown to be toxic to various doxorubicin-, methotrexate-, cisplastin-, topotecan-, melphalan-, etoposide-, and hydroxyurea-resistant cancer cell lines. Different cellular and molecular mechanisms may account for the lack of cross-resistance between anticancer agents and artemisinin compounds. It has been shown that overexpression of membrane protein pumps did not affect artemisinin’s toxicity toward cancer cells. On the other hand, artemisinin-resistant cancer cell lines have been reported by several laboratories.
Case Reports and Human Clinical Trials
Several case reports on effects of artemisinin compounds on cancer patients have been published. These include laryngeal squamous cell carcinoma/artesunate, metastatic uveal melanoma/artesunate, pituitary macroadenoma/artemether, non-small cell lung cancer/artesunate, and cervical cancer/dihydroar- temisinin. Artesunate has been tested in clinical trials for treatment of metastatic breast cancer and colorectal cancer.
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Encyclopedia of Cancer
DOI 10.1007/978-3-642-27841-9_7201-1 # Springer-Verlag Berlin Heidelberg 2014
Toxicity
Reports on toxicity of artemisinin compounds in humans are generally negligible. Side effects are generally mild. Brainstem neurotoxic has been reported in animals after long-term high-dose treatments and systemic administrations, e.g., IM. Lipid-soluble forms of artemisinin can be more neurotoxic than hydrophilic derivatives. However, toxicity of artemisinin-like compounds could occur with long-term use and has not been thoroughly investigated. Fetal developmental toxicity has been reported (Ades 2011).
Production of Artemisinin
Artemisinin has traditionally been produced from cultivated Artemisia annua L plants. Both crude extracts and pure artemisinin are available for applications in industry as well as for personal uses. Both yeast and bacteria have been genetically modified to produce artemisinic acid, a biosynthetic intermediate of artemisinin, that can be converted to artemisinin photochemically. Commercial produc- tion of artemisinin through the genetically engineered yeast has started in 2013. Artemisinin has been chemically synthesized, although its commercialization potential remains unclear (Corsello and Garg 2015).
Encyclopedia of Cancer
DOI 10.1007/978-3-642-27841-9_7201-1 # Springer-Verlag Berlin Heidelberg 2014
Cross-References
▶ Anti-Inflammatory Drugs
▶ Chelators as Anti-Cancer Drugs ▶ Drug Resistance
▶ Metastasis
References
Ades V (2011) Safety, pharmacokinetics and efficacy of artemisinins in pregnancy. Infect Dis Rep 3:e8 Corsello MA, Garg NK (2015) Synthetic chemistry fuels interdisciplinary approaches to the production of
artemisinin. Nat Prod Rep 32:359–366
Lai H, Singh NP, Sasaki T (2013) Development of artemisinin compounds for cancer treatment. Invest
New Drugs 31:230–246
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