Webmaster comments: This article by may be difficult to understand and in fact I hardly understand the technical terms in the reports. Yet they have enough clarity to prove Artemisinin is proven cancer killer and is less expensive, more powerful than presently used drugs and proven that it poses no problems for human consumption. It even kills some cancers with 100% effectiveness. If a pharmaceutical drug did a tenth of what Artemisinin does it would be front page news, yet it is not being prescribed and even suppressed in favor of less helpful drugs and surgery.

Report Report Since artemisinin is a relatively safe compound that causes no known side effects even at high oral doses, the present data indicate that artemisinin may be a potent cancer-chemoprevention agent.

Also see Artemisinin for General Cancer

What is Artemisinin?
Artemisinin is a natural extract from the roots of the Sweet wormwood plant and was used medically 2,000 yrs ago in China (called Qinghaosu ("ching-how-soo"). Today it is the drug of choice for multiple drug resistant malaria (MDR) by every medical establishment in the world except in the US. It is also beginning to be used very effectively against fast growing cancers in some countries. The World Health Organization recommends Artemisinin based therapy as the standard treatment for malaria worldwide. It has been used by millions and is safe, inexpensive, readily available and very effective.
Artemisinin is an extract containing all of the important natural chemicals in the Sweet wormwood plant however Artemisinin chemicals have been further separated into several natural and semi synthetic Artemisinin derivatives including; Dihydroartemisinin, Artesunate, Artemisinic Acid, Artemether and Arteether.

After reviewing a great deal of research on Artemisinin and its derivatives for years there are three things that are consistent. 1 The derivatives sometimes have a slight advantage in strength in a specific application. 2 Artemisinin has a much broader range of activity and usefulness than its derivatives because it contains all the active chemicals. 3 What ever the derivatives will do Artemisinin will do and often Artemisinin does it better.

How does Artemisinin work?Artemisinin has powerful positive effects on several cellular controls including at the DNA and mitochondrial level however Artemisinin is best known for its reaction to high levels of Iron.

Iron is necessary for cell replication and any fast growing type of cell needs vast amounts of Iron or it can’t grow. The malariaparasite sequesters (stores large amounts of) iron to grow and artemisinin kills the malaria parasite through the affinity of artemisinin to iron. Artemisinin has two oxygen atoms linked together in what is called an endoperoxide linkage. When exposed to free iron this linkage breaks down, forming very reactive free radicals, with rapid and extensive damage and death to the cell. This works regardless of most cell defenses so the toughest MDR malaria is easily killed.

Will Artemisinin kill Prostate cancer?

Quote from report #7 below "...provide a less toxic, inexpensive and effective cancer chemotherapy.provide a less toxic, inexpensive and effective cancer chemotherapy."

Artemisinin isn’t a stand-alone treatment but works well with many other things, of special interest is that Artemisinin, Retinol, Butyric acid and Vitamin D-3 dramatically amplify the effects of each other on cancer.

 All fast growing aggressive cancer cells sequester iron needed for their rapid cell division just as the malaria parasite does and arejust as easily killed. Evan the toughest multiple drug resistant cancers (MDR cancers) are vulnerable. Because normal healthy cells don’t have the high Iron load of fast growing cancer they are unaffected, unfortunately so are any slow growing or dormant cancer cells that must be killed by other means. Since even the worst types of prostate cancer usually have some slow growing cells then artemisinin may be useful for killing the fastest and most aggressive cells but other things must be used to finish the process.

Cautions; While taking artemisinin, foods with lots of antioxidants and antioxidant vitamins like Vit E must not be taken because the antioxidants will protect the cancer. Also radiation therapy damage releases free Iron in the system and artemisinin shouldn’t be used just before or just after radiation therapy.

Why isn’t Artemisinin FDA approved in the US? The FDA doesn’t work for free, every drug they approve is put through a very expensive certification process and someone must pay for it. The only people that can afford this are Pharmaceutical companies.

Because it costs approximately $800,000,000 (not a misprint) to get FDA approval, no pharmaceutical company will go for FDA approval on any natural compound unless they can totally control it. They must charge enough to get the $800 million back before they can make a profit and if other companies can supply the public with a cheaper version the original company will go broke. Since artemisinin is used worldwide (except in the US) no single company can control it, therefore it probably never will get FDA approval However pharmaceutical grade Artemisinin is inexpensive, effective, safe, legal, used everywhere in the world except the US and available in the US on the Internet.

Notes; The research below needs commentary and explanations added to make it more understandable but the demand for information is so high and available help is so limited that finishing this completely must wait until more help is available.

 There is no way to represent the research on artemisinin with just the 25 research summaries included below but to someone that understands what the big words and numbers mean its obvious Artemisinin is a powerful and safe cancer killer.
Things of interest have been underlined in the research below while important information is in bold and the most important information is in Bold and underlined.

 1: Curr Drug Targets. 2006 Apr;7(4):407-21.Related Articles, Links Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Efferth T. German Cancer Research Center, M070, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. t.efferth@dkfz.de

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.
PMID: 16611029

2: Head Neck. 2007 Apr;29(4):335-40.Related Articles, Links Effects of artemisinin and its derivatives on growth inhibition and apoptosis of oral cancer cells. Nam W, Tak J, Ryu JK, Jung M, Yook JI, Kim HJ, Cha IH. Department of Oral and Maxillofacial Surgery, College of Dentistry, Yonsei University, Seoul, Korea.

BACKGROUND: Artemisinin is of special biological interest because of its outstanding antimalarial activity. Recently, it was reported that artemisinin has antitumor activity. Its derivatives, artesunate, arteether, and artemeter, also have antitumor activity against melanoma, breast, ovarian, prostate, CNS, and renal cancer cell lines. Recently, monomer, dimer, and trimer derivatives were synthesized from deoxoartemisinin, and the dimers and the trimers were found to have much more potent antitumor activity than the monomers. METHODS: We evaluated the antitumor activity of artemisinin and its various derivatives (dihydroartemisinin, dihydroartemisinin 12-benzoate, 12-(2'-hydroxyethyl) deoxoartemisinin, 12-(2'-ethylthio) deoxoartemisinin dimer, deoxoartemisinin trimer) in comparison with paclitaxel (Taxol), 5-fluorouracil (5-FU), cisplatin in vitro. RESULTS: In this study, the deoxoartemisinin trimer had the most potent antitumor effect (IC(50) = 6.0 microM), even better than paclitaxel (IC(50) = 13.1 microM), on oral cancer cell line (YD-10B). In addition, it induced apoptosis through a caspase-3-dependent mechanism. CONCLUSION: The deoxoartemisinin trimer was found to have greater antitumor effect on tumor cells than other commonly used chemotherapeutic drugs, such as 5-FU, cisplatin, and paclitaxel. Furthermore, the ability of artemisinin and its derivatives to induce apoptosis highlights their potential as chemotherapeutic agents, for many anticancer drugs achieve their antitumor effects by inducing apoptosis in tumor cells. (c) 2006 Wiley Periodicals, Inc. PMID: 17163469

3: Int J Oncol. 2001 Apr;18(4):767-73. The anti-malarial artesunate is also active against cancer. Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR. Virtual Campus Rhineland-Palatinate, P.O. Box 4380, D-55033 Mainz, Germany.efferth@vcrp.de

Artesunate (ART) is a semi-synthetic derivative of artemisinin, the active principle of the Chinese herb Artemisia annua. ART reveals remarkable activity against otherwise multidrug-resistant Plasmodium falciparum and P. vivax malaria. ART has now been analyzed for its anti-cancer activity against 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute, USA. ART was most active against leukemia and colon cancer cell lines(mean GI50 values: 1.11+/-0.56 microM and 2.13+/-0.74 microM , respectively). Non-small cell lung cancer cell lines showed the highest mean GI50 value (25.62+/-14.95 microM) indicating the lowest sensitivity towards ART in this test panel. Intermediate GI50 values were obtained for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines. Importantly, a comparison of ART's cytotoxicity with those of other standard cytostatic drugs showed that ART was active in molar ranges comparable to those of established anti-tumor drugs. Furthermore, we tested CEM leukemia sub-lines resistant to either doxorubicin, vincristine, methotrexate, or hydroxyurea which do not belong to the N.C.I. screening panel. None of these drug-resistant cell lines showed cross resistance to ART. To gain insight into the molecular mechanisms of ART's cytotoxicity, we used a panel of isogenic Saccaromyces cerevisiae strains with defined genetic mutations in DNA repair, DNA checkpoint and cell proliferation genes. A yeast strain with a defective mitosis regulating BUB3 gene showed increased ART sensitivity and another strain with a defective proliferation-regulating CLN2 gene showed increased ART resistance over the wild-type strain, wt644. None of the other DNA repair or DNA check-point deficient isogenic strains were different from the wild-type. These results and the known low toxicity of ART are clues that ART may be a promising novel candidate for cancer chemotherapy. PMID: 11251172

4: Cancer Lett. 2006 Jan 8;231(1):43-8.Related Articles, Links Oral artemisinin prevents and delays the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in the rat. Lai H, Singh NP. Department of Bioengineering, University of Washington, Box 357962, Seattle, WA 98195-7962, USA. hlai@u.washington.edu

Artemisinin, a compound isolated from the sweet wormwood Artemisia annua L., has previously been shown to have selective toxicity towards cancer cells in vitro. In the present experiment, we studied the potential of artemisinin to prevent breast cancer development in rats treated with a single oral dose (50mg/kg) of 7,12-dimethylbenz[a]anthracene (DMBA), known to induce multiple breast tumors. Starting from the day immediately after DMBA treatment, one group of rats was provided with a powdered rat-chow containing 0.02% artemisinin, whereas a control group was provided with plain powdered food. For 40 weeks, both groups of rats were monitored for breast tumors. Oral artemisinin significantly delayed (P<.002) and in some animals prevented (57% of artemisinin-fed versus 96% of the controls developed tumors, P<.01) breast cancer development in the monitoring period. In addition, breast tumors in artemisinin-fed rats were significantly fewer (P<.002) and smaller in size (P<.05) when compared with controls. Since artemisinin is a relatively safe compound that causes no known side effects even at high oral doses, the present data indicate that artemisinin may be a potent cancer-chemoprevention agent. PMID: 16356830

5: Drug Resist Updat. 2005 Feb-Apr;8(1-2):85-97.Related Articles, Links Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. Efferth T. German Cancer Research Center, M070, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. thomas.efferth@web.de

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.PMID: 15878303
 
6: Planta Med. 2007 Apr;73(4):299-309. Epub 2007 Mar 12.Related Articles, Links Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin--from bench to bedside. Efferth T. German Cancer Research Center, Heidelberg, Germany. t.efferth@dkfz.de

Secondary metabolites from plants serve as defense against herbivores, microbes, viruses, or competing plants. Many medicinal plants have pharmacological activities and may, thus, be a source for novel treatment strategies. During the past 10 years, we have systematically analyzed medicinal plants used in traditional Chinese medicine and focused our interest on Artemisia annua L. (qinhao, sweet wormwood). We found that the active principle of Artemisia annua L., artemisinin, exerts not only antimalarial activity but also profound cytotoxicity against tumor cells. The inhibitory activity of artemisinin and its derivatives towards cancer cells is 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. The identified genes are from classes with diverse biological functions; 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, NF-kappaB). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Antioxidant stress genes (thioredoxin, catalase, gamma-glutamylcysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines overexpressing genes that confer resistance to established antitumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that artesunate is not involved in multidrug resistance. The anticancer activity of artesunate has also been shown in human xenograft tumors in mice. First encouraging experience in the clinical treatment of patients suffering from uveal melanoma calls for comprehensive clinical trials with artesunate for cancer treatment in the near future. PMID: 17354163
 
 7: Anticancer Res. 2005 Nov-Dec;25(6B):4325-31.Related Articles, Links Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells. Singh NP, Lai HC. Department of Bioengineering, Box 357962, University of Washington, Seattle, WA 98195-7962, USA. Narendra@u.washington.edu

BACKGROUND: Butyric acid is a short chain fatty acid produced by large bowel bacterial flora. It serves as an antiinflammatory agent and nutrient for normal colon cells. Butyric acid has also been shown to induce apoptosis in colon and many other cancer cells. Artemisinin is a compound extracted from the wormwood Artemisia annua L. It has been shown to selectively kill cancer cells in vitro and to be effective in treating animal and human cancer. We and others have found that the artemisinin analog, dihydroartemisinin (DHA), kills cancer cells by apoptosis. In the present study, the efficacy of a combined treatment of DHA and butyric acid at low doses in killing cancer cells was investigated. MATERIALS AND METHODS: Molt-4 cells (a human lymphoblastoid leukemia cell line) and freshly isolated human lymphocytes, cultured in complete RPMI-1640 medium, were first incubated with 12 microM of human holotransferrin at 37 degrees C in a humid atmosphere of 5% CO2 for one hour to enhance the iron concentration in the cells. Cells from each cell type were then divided into 20 flasks. These flasks were grouped into four sets of five cultures each. Zero, 5, 10 or 20 microM of DHA was added, respectively, to these sets and the cells were incubated at 37 degrees C for one hour. Zero, 1, 5, 10, or 20 mM of sodium butyrate was then added to the five cultures of each set, respectively. Thus, the treatments involved a combination of 4 doses of DHA and 5 doses of sodium butyrate. The cells were counted immediately before the addition of DHA, and at 24 and 48 hours after the addition of sodium butyrate. RESULTS: DHA alone at the 24-hour time-point and 20 microM concentration significantly reduced the number of Molt-4 cells in the culture by approximately 40% (p < 0.001, compared to non-treated control), whereas it did not significantly affect the number of normal human lymphocytes. Similarly, 1 mM sodium butyrate alone at 24 hours reduced the number of Molt-4 cells by approximately 32% (p < 0.001, compared to non-treated control), without significantly affecting normal human lymphocytes. The combination of 20 microM DHA and 1 mM sodium butyrate killed all Molt-4 cells at the 24-hour time-point and did not significantly affect lymphocytes. CONCLUSION: DHA in combination with butyric acid acts synergistically at low doses. The combination may provide a less toxic, inexpensive and effective cancer chemotherapy. PMID: 16309236
 
 8: Eur J Pharmacol. 2003 Dec 15;482(1-3):67-76.Related Articles, Links Differential involvement of protein kinase C in human promyelocytic leukemia cell differentiation enhanced by artemisinin. Kim SH, Kim HJ, Kim TS. College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Kwangju 500-757, South Korea.

Artemisinin, a sesquiterpene lactone endoperoxide that exists in several medicinal plants, is a well-known anti-malarial agent. In this report, we investigated the effect of artemisinin on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Artemisinin markedly increased the degree of HL-60 leukemia cell differentiation when simultaneously combined with low doses of 1 alpha,25-dihydoxyvitamin D(3) [1,25-(OH)(2)D(3)] or all-trans retinoic acid (all-trans RA). Artemisinin by itself had very weak effects on the differentiation of HL-60 cells. Cytofluorometric analysis and cell morphologic studies indicated that artemisinin potentiated 1,25-(OH)(2)D(3)-induced cell differentiation predominantly into monocytes and all-trans RA-induced cell differentiation into granulocytes, respectively. Extracellular-regulated kinase (ERK) inhibitors markedly inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)(2)D(3) or all-trans RA, whereas phosphatidylinositol 3-kinase (PI3-K) inhibitors did not. Particularly, protein kinase C (PKC) inhibitors inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)(2)D(3) but not with all-trans RA. Artemisinin enhanced PKC activity and protein level of PKC beta I isoform in only 1,25-(OH)(2)D(3)-treated HL-60 cells. Taken together, these results indicate that artemisinin strongly enhanced 1,25-(OH)(2)D(3)- and all-trans RA-induced cell differentiation in which PKC is differentially involved in arteminisin-mediated enhancement of leukemia cell differentiation.
PMID: 14660006
 
9: Oncol Rep. 2005 Dec;14(6):1599-603.Related Articles, Links Artesunate in the treatment of metastatic uveal melanoma--first experiences. Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, Schuler G. Department of Dermatology, University Hospital of Erlangen, Erlangen, Germany. thomas.berger@derma.imed.uni-erlangen.de

Artesunate (ART) is a derivative of artemisinin, the active principle of the Chinese herb Artemisia annua L. Artesunate is approved for the treatment of multidrug-resistant malaria and has an excellent safety profile. It has been shown that Artesunate, apart from its anti-malarial activity, has cytotoxic effects on a number of human cancer cell lines, including leukemia, colon cancer and melanoma. We report on the first long-term treatment of two cancer patients with ART in combination with standard chemotherapy. These patients with metastatic uveal melanoma were treated on a compassionate-use basis, after standard chemotherapy alone was ineffective in stopping tumor growth. The therapy-regimen was well tolerated with no additional side effects other than those caused by standard chemotherapy alone. One patient experienced a temporary response after the addition of ART to Fotemustine while the disease was progressing under therapy with Fotemustine alone. The second patient first experienced a stabilization of the disease after the addition of ART to Dacarbazine, followed by objective regressions of splenic and lung metastases. This patient is still alive 47 months after first diagnosis of stage IV uveal melanoma, a situation with a median survival of 2-5 months. Despite the small number of treated patients, ART might be a promising adjuvant drug for the treatment of melanoma and possibly other tumors in combination with standard chemotherapy. Its good tolerability and lack of serious side effects will facilitate prospective randomized trials in the near future. PMID: 16273263
 
10: Phytother Res. 2005 May;19(5):428-32.Related Articles, Links Cytotoxicity of some Russian ethnomedicinal plants and plant compounds. Spiridonov NA, Konovalov DA, Arkhipov VV. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia. spiridonov@cber.fda.gov

The cytotoxic action of crude ethanol extracts from 61 plant species used in Russian ethnomedicine for alleviating symptoms of diseases in cancer patients was studied on cultured human lymphoblastoid Raji cells. Extracts from Chelidonium majus, Potentilla erecta, Chamaenerium angustfolium, Filipendula ulmaria and Inula helenium possessed marked cytotoxicity, suppressing the growth of the cells at concentrations of 10 and 50 microg/mL. The cytotoxicity of purified active compounds from selected plant species was evaluated along with pharmaceutical antineoplastic drugs methotrexate, fluorouracil, cyclophosphamide and vinblastine. Sesquiterpene lactones helenin, telekin and artemisinin, aromatic polyacetylene capillin, and alkaloid preparation sanguirythrine suppressed cell growth at concentrations of 1-2 microg/mL, which exceeds the cytotoxicity of cyclophosphamide and fluorouracil. Copyright (c) 2005 John Wiley & Sons, Ltd. PMID: 16106386
 
11: Anticancer Res. 2004 Jul-Aug;24(4):2277-80. Artemisinin induces apoptosis in human cancer cells. Singh NP, Lai HC.
Department of Bioengineering, University of Washington, Seattle, Washington 98195-7962, USA. Narendra@u.washington.edu

BACKGROUND: Artemisinin is a chemical compound extracted from the wormwood plant, Artemisia annua L. It has been shown to selectively kill cancer cells in vitro and retard the growth of implanted fibrosarcoma tumors in rats. In the present research, we investigated its mechanism of cytotoxicity to cancer cells. MATERIALS AND METHODS: Molt-4 cells, in complete RPMI-1640 medium, were first incubated with 12 microM of human holotransferrin at 37 degrees C in a humid atmosphere of 5% CO2 for one hour. This enhanced the iron supply to the cells. The cells were then pelleted and transferred to a complete RPMI-1640 containing 200 microM of an analog dihydroartemisinin (DHA) and incubation was started (0h). In addition, some culture samples were treated with holotransferrin alone and some (controls) were assayed without neither holotransferrin nor DHA treatment. Cells were counted and DNA diffusion assay was used to evaluate apoptosis and necrosis in each sample at 0 h and at 1, 2, 4 and 8 h of incubation. RESULTS: DHA treatment significantly decreased cell counts and increased the proportion of apoptosis in cancer cells compared to controls (chi2=4.5, df=1, p<0.035). Addition of holotransferrin significantly further decreased cell counts (chi2=4.5, df=1, p<0.035) and increased apoptosis (chi2=4.5, df=1, p<0.035). No necrotic cells were observed. CONCLUSION: This rapid induction of apoptosis in cancer cells after treatment with DHA indicates that artemisinin and its analogs may be inexpensive and effective cancer agents. PMID: 15330172
 
12: Anticancer Res. 2004 Jul-Aug;24(4):2153-60. Artemisinin: an alternative treatment for oral squamous cell carcinoma.
Yamachika E, Habte T, Oda D. Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Washington, Box 357134, Seattle, WA 98195-7134, USA.

Artemisinin (AR) is a widely used antimalarial drug. Recently, additional uses for AR as an anticancer drug were discovered. Using TUNEL, immunohistochemistry (IHS) markers and flow cytometry techniques, we evaluated the effect of AR and 5-FU on HPV 16 immortalized and transformed human gingival epithelial (IHGK) cells. The results of TUNEL showed that AR-treated IHGK cells consisted of 82% positive cells, while 5-FU-treated cells consisted of 18% positive cells. The IHS markers demonstrated positive staining with Bax p53, CD40 and CD40L in AR-treated cells and negative staining with Bcl-2. 5-FU-treated cells demonstrated a profile similar to AR but with less intensity. Cell cycle by flow cytometry results showed that only 5-FU-treated cells demonstrated a significant S-phase rate increase to 45%. In conclusion, our results indicate that AR is cytotoxic to transformed oral epithelial cells through apoptosis, while 5-FU is cytotoxic primarily through cell toxicity. PMID: 15330155
 
13: Biochem Pharmacol. 2004 Jul 1;68(1):3-10. Oxidative stress response of tumor cells: microarray-based comparison between artemisinins and anthracyclines. Efferth T, Oesch F. Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. thomas.efferth@web.de

The antimalarial artemisinins also reveal profound cytotoxic activity against tumor cells. Artemisinins harbor an endoperoxide bridge whose cleavage results in the generation of reactive oxygen species (ROS) and/or artemisinin carbon-centered free radicals. Established cancer drugs such as anthracyclines also form ROS and free radicals that are responsible for the cardiotoxicity of anthracyclines. In contrast, artemisinins do not reveal cardiotoxicity. In the present investigation, we compared the cytotoxic activities of different artemisinins (artemisinin, artesunate, arteether, artemether, artemisitene, dihydroartemisinylester stereoisomers) in 60 cell lines of the National Cancer Institute (NCI), USA, with those of anthracyclines (doxorubicin, daunorubicin, 4'-epirubicin, idarubicin, deoxydoxorubicin, trifluoroacetyl-doxorubicin-14-valerate). The inhibition concentration 50% (IC(50)) values of artemisinins and anthracyclines were correlated with the mRNA expression of 170 genes involved in oxygen stress response and metabolism as recently determined by microarray analysis and deposited in the NCI database (http://dtp.nci.nih.gov). The genes whose expression was significantly linked to cellular drug response in Kendall's tau tests were subjected to hierarchical cluster analysis and cluster image mapping. Mathematical correction for false-positive correlations was done by a false discovery rate algorithm. One cluster contained predominantly genes with a relationship to artemisinins and another one genes with a relationship to anthracyclines. In a third cluster, genes correlating to both drug classes were assembled. This indicates that different sets of genes involved in oxidative stress response and metabolism may contribute to the cytotoxic and differing toxic side effects of these drug classes. PMID: 15183112
 
14: Pharmacology. 2004 May;71(1):1-9. Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Chen HH, Zhou HJ, Wu GD, Lou XE. Department of Clinical Pharmacology, The First Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, PR China. chenh552@163.com

Artesunate (ART) is a semi-synthetic derivative of artemisinin extracted from the plant Artemisia annua is a safe and effective antimalarial drug. In the present investigation, ART was found also to inhibit angiogenesis in vivo and in vitro. The anti-angiogenic effect in vivo was evaluated in nude mice by means of human ovarian cancer HO-8910 implantation and immunohistochemical stainings for microvessel (CD(31)), vascular endothelial growth factor (VEGF) and VEGF receptor KDR/flk-1. Tumor growth was decreased and microvessel density was reduced following drug treatment with no apparent toxicity to the animals. ART also remarkably lowered VEGF expression on tumor cells and KDR/flk-1 expression on endothelial cells as well as tumor cells. The in vitro effect of ART was tested on models of angiogenesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). The results showed that ART significantly inhibited angiogenesis in a dose-dependent form in the range of 0.5 approximately 50 micromol/l. Additionally, the inhibitory effect of ART on HVUEC proliferation was stronger than that on Hela, JAR, HO-8910 cancer cells, NIH-3T3 fibroblast cells and human endometrial cells, indicating that ART was selectively against HUVEC. These findings and the known low toxicity of ART are clues that ART may be a promising angiogenesis inhibitor. Copyright 2004 S. Karger AG, Basel PMID: 15051917
 
15: Med Hypotheses. 2003 Oct;61(4):509-11. Turning an 'Achilles' Heel' into an asset--activation of HIF-1alpha during angiostatic therapy will increase tumor sensitivity to iron-catalyzed oxidative damage. McCarty MF. Pantox Laboratories, San Diego, California 92109, USA. mccarty@pantox.com

During angiostatic therapy, tumor hypoxia will activate the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), and will select for mutations which up-regulate the activity of this factor. This adaptation will increase tumor angiogenic capacity, while aiding the survival of poorly nourished cancer cells. A further effect of HIF-1alpha is to increase expression of transferrin receptors. The natural antimalarial drug artemisinin is selectively toxic to iron-loaded cells (such as malarial parasites), and it has recently been suggested that, inasmuch as many cancers overexpress transferrin receptors, such cancers might be treatable with a regimen comprised of iron supplementation and high-dose artemisinin. Thus, it can be anticipated that many tumors which evolve relative resistance to angiostatic therapy will be selectively susceptible to attack by the iron-loading/artemisinin strategy. PMID: 13679021
 
16: Pharmacol Res. 2003 Sep;48(3):231-6. Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. Chen HH, Zhou HJ, Fang X. Department of Pharmacology and Toxicology, College of Pharmacology, Zhejiang University, Zhejiang 310031, Hangzhou, PR China. chenh552@163.com

Artemisinin derivatives artesunate (ART) and dihydroartemisinin are remarkable anti-malarial drugs with low toxicity to humans. In the present investigation, we find they also inhibited tumor cell growth and suppressed angiogenesis in vitro. The anti-cancer activity was demonstrated by inhibition (IC(50)) of four human cancer cell lines: cervical cancer Hela, uterus chorion cancer JAR, embryo transversal cancer RD and ovarian cancer HO-8910 cell lines growth by the MTT assay. IC(50) values ranged from 15.4 to 49.7 microM or from 8.5 to 32.9 microM after treatment with ART or dihydroartemisinin for 48 h, indicating that dihydroartemisinin was more effective than ART in inhibiting cancer cell lines. The anti-angiogenic activities were tested on in vitro models of angiogenesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial (HUVE) cells. We investigated the inhibitory effects of ART and dihydroartemisinin on HUVE cells proliferation by cell counting, migration into the scratch wounded area in HUVE cell monolayers and microvessel tube-like formation on collagen gel. The results showed ART and dihydroartemisinin significantly inhibited angiogenisis in a dose-dependent form in range of 12.5-50 microM and 2.5-50 microM, respectively. They indicated that dihydroartemisinin was more effective than ART in inhibiting angiogenesis either. These results and the known low toxicity are clues that ART and dihydroartemisinin may be promising novel candidates for cancer chemotherapy.
PMID: 12860439
 
17: Biol Pharm Bull. 2002 Dec;25(12):1555-61. Modulation of multidrug resistance by artemisinin, artesunate and dihydroartemisinin in K562/adr and GLC4/adr resistant cell lines. Reungpatthanaphong P, Mankhetkorn S. Laboratory of Physical Chemistry, Molecular and Cellular Biology, Faculty of Science, Burapha University, Bangsaen, Chonburi, Thailand.

Overcoming MDR (multidrug resistance) phenomena is a crucial aspect of cancer chemotherapy research. Artemisinin and its derivatives have been found to inhibit the proliferation of cancer cells in the microM range. They poorly inhibited the function of P-glycoprotein and did not inhibit the function of MRP1-protein. The concentrations required to inhibit by 50% the function of P-glycoprotein are 110+/-5 microM. Artemisinin, artesunate and dihydroartemisinin efficiently decreased the mitochondrial membrane potential, leading to a decrease in intracellular ATP in all cell lines tested: by 30 to 50% at 5 microM. Artemisinin, artesunate and dihydroartemisinin increased cytotoxicity of pirarubicin and doxorubicin in P-glycoprotein-overexpressing K562/adr, and in MRP1-overexpressing GLC4/adr, with the delta(0.5) ranging from 200 to 860 nM, but not in their corresponding drug-sensitive cell lines. In this range of concentrations these compounds did not decrease the function of P-glycoprotein, suggesting a mechanism by which the drugs did not reverse MDR phenomenon at the P-glycoprotein level but at the mitochondrial level. PMID: 12499639
 
18: Biochem Pharmacol. 2002 Aug 15;64(4):617-23. mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether. Efferth T, Olbrich A, Bauer R. Virtual Campus Rhineland-Palatinate, P.O. Box 4380, 55033 Mainz, Germany. efferth@vcrp.de

The antimalarial artemisinin derivatives artesunate (ART), arteether (ARE), and artemether (ARM) reveal remarkable antineoplastic activity. In the present investigation, we identified mRNA expression profiles associated with the response of tumor cells to ART, ARE, and ARM. We performed correlation and hierarchical cluster analyses of inhibition concentration 50% (IC(50)) values and basal mRNA expression levels of 464 genes deposited in the database of the National Cancer Institute, USA. Correlating IC(50) values of ART, ARE, and ARM and of 16 established antineoplastic drugs revealed that the artemisinin derivatives could not be assigned with a known class of drugs with defined mode(s) of action. The basal mRNA expression of 208 out of 464 genes (45%) correlated significantly with IC(50) values of at least one artemisinin derivative. These genes were from different classes (drug resistance genes, DNA damage and repair genes, apoptosis-regulating genes, proliferation-associated genes, oncogenes, tumor suppressor genes and cytokines). We identified two different gene clusters by hierarchical cluster analysis. One cluster contained predominately genes significantly correlated to all three artemisinin derivatives. This overlapping set of genes points to common molecular mechanisms of tumor inhibition by all three drugs in which genes affecting cellular proliferation may play an important role. The second cluster contained genes differentially associated with the response of artemisinin derivatives to cancer cells. The number of correlating drug resistance genes in this cluster increased in the order ART<ARE<ARM and was paralleled by increasing IC(50) values of the three drugs in the same order. The higher activity of ART in comparison to ARE and ARM may, thus, be explained by a lower number of drug resistance genes affecting ARTs action. The present analysis is a starting point for the generation of hypotheses on candidate genes and for a more detailed dissection of the functional role of individual genes for the activity of artemisinin derivatives in tumor cells. PMID: 12167480
 
19: Int J Cancer. 2002 Feb 10;97(5):700-5. Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Mukanganyama S, Widersten M, Naik YS, Mannervik B, Hasler JA. Department of Biochemistry, University of Zimbabwe, Harare, Zimbabwe.

A strategy to overcome multidrug resistance in cancer cells involves treatment with a combination of the antineoplastic agent and a chemomodulator that inhibits the activity of the resistance-causing protein. The aim of our study was to investigate the effects of antimalarial drugs on human recombinant glutathione S-transferase (GSTs) activity in the context of searching for effective and clinically acceptable inhibitors of these enzymes. Human recombinant GSTs heterologously expressed in Escherichia coli were used for inhibition studies. GST A1-1 activity was inhibited by artemisinin with an IC(50) of 6 microM, whilst GST M1-1 was inhibited by quinidine and its diastereoisomer quinine with IC(50)s of 12 microM and 17 microM, respectively. GST M3-3 was inhibited by tetracycline only with an IC(50) of 47 microM. The IC(50) values obtained for GSTP1-1 was the most susceptible enzyme to inhibition by antimalarials with IC(50)values of 1, 2, 1, 4, and 13 microM for pyrimethamine, artemisinin, quinidine,quinine and tetracycline, respectively. artemisinin, quinine, quinidine and tetracycline are below peak plasma concentrations obtained during therapy of malaria with these drugs. It seems likely, therefore, that GSTs may be inhibited in vivo at doses normally used in clinical practice. Using the substrate ethacrynic acid, a diuretic drug also used as a modulator to overcome drug resistance in tumour cells, GST P1-1 activity was inhibited by tetracycline, quinine, pyrimethamine and quinidine with IC(50) values of 18, 27, 45 and 70 microM, respectively. The ubiquitous expression of GSTs in different malignancies suggests that the addition of nontoxic reversing agents such as antimalarials could enhance the efficacy of a variety of alkylating agents. Copyright 2001 Wiley-Liss, Inc. PMID: 11807801
 
20: Life Sci. 2001 Nov 21;70(1):49-56. Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Singh NP, Lai H. Department of Bioengineering, University of Washington, Seattle 98195-7962, USA. narendra@u.washington.edu

Artemisinin becomes cytotoxic in the presence of ferrous iron. Since iron influx is high in cancer cells, artemisinin and its analogs selectively kill cancer cells under conditions that increase intracellular iron concentrations. We report here that after incubation with holotransferrin, which increases the concentration of ferrous iron in cancer cells, dihydroartemisinin, an analog of artemisinin, effectively killed a type of radiation-resistant human breast cancer cell in vitro. The same treatment had considerably less effect on normal human breast cells. Since it is relatively easy to increase the iron content inside cancer cells in vivo, administration of artemisinin-like drugs and intracellular iron-enhancing compounds may be a simple, effective, and economical treatment for cancer. PMID: 11764006
 
21: Planta Med. 1998 Oct;64(7):615-9. Artemisinin-derived sesquiterpene lactones as potential antitumour compounds: cytotoxic action against bone marrow and tumour cells. Beekman AC, Wierenga PK, Woerdenbag HJ, Van Uden W, Pras N, Konings AW, el-Feraly FS, Galal AM, Wikstrom HV. Department of Pharmaceutical Biology, Groningen Institute for Drug Studies, University of Groningen, The Netherlands.

We determined the in vitro cytotoxic activity of the sesquiterpene lactone endoperoxide artemisinin (1) and some chemically prepared derivatives, which have been found to display cytotoxicity to cloned murine Ehrlich ascites tumour (EAT) cells and human HeLa cells and against murine bone marrow using a clonogenic assay for committed progenitor cells of the granulocyte-monocyte lineage (CFU-GM assay). Comparing artemisinin (1) to deoxyartemisinin (2), the endoperoxide group appeared to play a role in cytotoxicity to CFU-GM cells. Dimers of dihydroartemisinin and dihydrodeoxyartemisinin revealed that the stereochemistry of the ether linkage of the dimers was a more important determinant for this cytotoxic activity. The nonsymmetrical dimer of dihydroartemisinin (3) and the corresponding endoperoxide-lacking dimer of dihydrodeoxyartemisinin (5) were equally cytotoxic to CFU-GM cells. Despite the differences between both systems, it may be stated that most compounds displayed higher cytotoxicity to CFU-GM cells than to EAT cells. Dimers of dihydroartemisinin (3, 4) were selected as potential antitumour compounds and subjected to the National Cancer Institute drug-screening programme consisting of about sixty human cancer cell lines derived from nine different tissues. Both compounds displayed the same specific cytotoxicity pattern. Throughout the screen dimer 3 was more active than 4. PMID: 9810267
 
22: Planta Med. 1994 Feb;60(1):54-7. Cytotoxic terpenoids and flavonoids from Artemisia annua. Zheng GQ. LKT Laboratories, Inc., Minneapolis, MN 55414.

The cytotoxic activity of nine terpenoids and flavonoids isolated from Artemisia annua was tested in vitro on several human tumor cell lines. These compounds are artemisinin, deoxyartemisinin, artemisinic acid, arteannuin-B, stigmasterol, friedelin, friedelan-3 beta-ol, artemetin, and quercetagetin 6,7,3',4'-tetramethyl ether. Friedelane-type triterpenoids were isolated for the first time from this plant. Artemisinin and quercetagetin 6,7,3',4'-tetramethyl ether showed significant cytotoxicity against P-388, A-549, HT-29, MCF-7, and KB tumor cells. PMID: 8134418
 
23: Zhongguo Yao Li Xue Bao. 1992 Nov;13(6):541-3. Erratum in:Chung Kuo Yao Li Hsueh Pao 1993 Mar;14(2):192.
[Antitumor activities of 4 derivatives of artemisic acid and artemisinin B in vitro] [Article in Chinese] Sun WC, Han JX, Yang WY, Deng DA, Yue XF. Shanghai institute of Materia Medica, Chinese Academy of Sciences.

 The cytotoxicities of 2 derivatives of artemisinin B and 2 derivatives of artemisic acid (designated as Compound A, B, C, and D) were investigated, using trypan blue dye exclusion test and colony-forming units assay. At the concentration of 5 micrograms.ml-1, the inhibition rates of these 4 compounds against murine leukemia cell line P388 were > 85%. When tested against human hepatoma cell line SMMC-7721 at 25 micrograms.ml-1, the inhibition rates of Compound A, B, C, and D were found to be 92.3%, 96.9%, 84%, and 82.1%, respectively, and 27%, 8%, 37.8%, 1.7% against normal human embryonic lung cell line WI-38, respectively. These 4 compounds all showed an inhibition rate of 100% against human gastric cancer cell line SGC-7901 at 50 micrograms.ml-1. PMID: 1302444
 
24: Anticancer Res. 2004 Mar-Apr;24(2A):495-500. Activity of novel plant extracts against medullary thyroid carcinoma cells. Rinner B, Siegl V, Purstner P, Efferth T, Brem B, Greger H, Pfragner R. Department of Pathophysiology, Medical University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing tumor, derived from the parafollicular C-cells of the thyroid. MTC is known to be relatively insensitive to conventional chemotherapy. MATERIALS AND METHODS: Eight cell lines were established from MTCs; each showed an up-regulation of Bcl-2. We investigated ten agents from plants of the genera Stemona (Stemonaceae), Aglaia (Meliaceae) and Artemisia (Asteraceae) for their effects on proliferation and apoptotic rates. Extracts have been used in traditional Chinese medicine; however, no experience on their effects on medullary thyroid carcinomas has been reported so far. Growth kinetics and viability were examined using the Casy-1-Cell Counter & Analyzer and the WST-1-based cytotoxicity assay. Apoptosis was studied by DAPI staining, by measurement of caspase-3 activity and Bcl-2 expression. RESULTS: A strong antiproliferative effect was recognized in each Aglaia species and with Artesunate, whereas an enhancement of apoptosis was provoked particularly by Stemona tuberosa Lour. CONCLUSION: The activity of the novel plant extracts possiby offers a new approach towards successful chemotherapy of the so far chemo-resistant medullary thyroid carcinoma. PMID: 15152949
 
25: Pharmacogenomics J. 2006 Jul-Aug;6(4):269-78. Epub 2006 Jan 24.Related Articles, Links Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Anfosso L, Efferth T, Albini A, Pfeffer U. Experimental Oncology A, National Cancer Research Institute, Genova, Italy.

Artemisinin (ARS) and its derivatives are used for the second-line therapy of malaria infections with Plasmodium falciparum and P. vivax. ARSs also reveal profound antitumor activity in vitro and in vivo. In the present investigation, we correlated the mRNA expression data of 89 angiogenesis-related genes obtained by microarray hybridization from the database of the US National Cancer Institute with the 50% growth inhibition concentration values for eight ARSs (ARS, arteether (ARE), artesunate (ART), artemisetene, arteanuine B, dihydroartemisinylester stereoisomers 1 and 2). The constitutive expression of 30 genes correlated significantly with the cellular response to ARSs. By means of hierarchical cluster analysis and cluster image mapping expression, profiles were identified that determined significantly the cellular response to ART, ARE, artemether and dihydroartemisinylester stereoisomer 1. We have exemplarily validated the microarray data of six out of these 30 genes by real-time RT-PCR in seven cell lines. The fact that sensitivity and resistance of tumor cells could be predicted by the mRNA expression of angiogenesis-related genes indicate that ARSs reveal their antitumor effects at least in part by inhibition of tumor angiogenesis. As many chemopreventive drugs exert antiangiogenic features, ARSs might also be chemopreventive in addition to their cytotoxic effects. PMID: 16432535