Artemisinin Super 180mg 60 Vcaps

A topic of research in cancer.

Artemisinin induces apoptosis in human cancer cells.

Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells.

Pharmacological Research 48 (2003) 231–236
Inhibition of human cancer cell line growth and human umbilical vein
endothelial cell angiogenesis by artemisinin derivatives in vitro
Huan-Huan Chen∗, Hui-Jun Zhou, Xin Fang
Department of Pharmacology and Toxicology, College of Pharmacology, Zhejiang University, Hangzhou, Zhejiang 310031, PR China
Accepted 30 March 2003
Abstract
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 activitywas demonstrated
by inhibition (IC50) 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. IC50 values ranged from 15.4 to 49.7
M or from 8.5 to 32.9
M after
treatment with ART or dihydroartemisinin for 48 h, indicating that dihydroartemisininwasmore 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 ofARTand dihydroartemisinin onHUVEcells proliferation
by cell counting, migration into the scratchwounded area inHUVEcell 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
M
and 2.5–50
M, 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.
© 2003 Elsevier Science Ltd. All rights reserved.
Keywords: Artesunate; Dihydroartemisinin; Tumor; Angiogenesis; Tube formation
1. Introduction
Artemisinin and its derivatives such as artesunate (ART)
and dihydroartemisinin distinguish themselves as a new
generation of anti-malarial drugs with low toxicity. Having
been used for the treatment of more than one million cases
of malarial infection, artemisinin and its analogs are considered
as safe drugs with no obvious adverse reaction or noticeable
side effects [1]. Especially, artemisinin derivatives
exert remarkable activity against otherwise drug-resistant
plasmodium falciparum and plasmodium vivax strains
[2–4]. Thus, they are gaining increasing importance in the
treatment of malarial infection.
Recently, it is reported that the anti-malarial artemisinin
derivatives are also active against tumor cells. Some investigators
found artemisinin drugs had inhibitory effects on
cancer cell growth such as lung, malanomas, breast, renal,
prostate, CNS cancer cells including many drug-resistant
cancer cells [5,6]. Moreover, they also have suppressive
∗ Corresponding author. Tel.: +86-571-87217206;
fax: +86-571-88075447.
E-mail address: chenh552@163.com (H.-H. Chen).
effects on the growth of human tumor xenografts in rat,
mice and nude mice [7,8]. These studies indicated that
artemisinin derivatives have anti-cancer activities in vitro
and in vivo.
It is known that tumors are angiogenesis dependent and
can elicit the production by a new capillary endothelium
from the host by themselves [9]. Angiogenesis, the proliferation
and migration of endothelial cells (ECs) resulting in
the formation of new blood vessels, is a vital process for the
progression of all solid tumors from a small, localized focus
to an enlarging tumor with the capability to metastasize
[10,11]. Consequently, inhibition of angiogenesis may lead
to control of tumor growth and metastasis [12]. In cancer
therapy, cancer inhibitors which have the anti-angiogenic
activity as well as anti-cancer activity may kill cancer much
more effectively. Artemisinin derivatives have been suggested
to have anti-tumor activity. However, anti-angiogenic
activity has not yet been demonstrated.
In the present study, we have investigated whether
artemisinin derivatives ART and dihydroartemisinin have the
anti-angiogenic activity as well as the anti-tumor activity.We
tested the inhibitory effects of ART and dihydroartemisinin
on human cervical cancer Hela, uterus chorion cancer
1043-6618/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S1043-6618(03)00107-5
232 H.-H. Chen et al. / Pharmacological Research 48 (2003) 231–236
JAR, embryo transversal cancer RD and ovarian cancer
HO-8910 cell lines growth and the proliferation, migration,
tube formation of human umbilical vein endothelial cells
(HUVECs).
2. Materials and methods
2.1. Materials
ART was purchased from Guiling Pharmaceutical Co.
(Guangxi, China) and dihydroartemisinin was a gift from
the Engineer, Liuxu of Guiling Pharmaceutical Co. Collagen
(Type I) was purchased from Sigma (Bornem, Belgium),
RPMI 1640 medium, Dulbecco’s modified eagle’s medium
(DMEM) were supplied by Gibco (BRL, Merelbeke, Belgium).
HEPES, DMSO, penicillin, streptomycin, MTT
and EC growth factor (VEGF) were obtained from Sigma
Chemical Co. (St. Louis, MO, USA).
Four human cancer cell lines: cervical cancer Hela, uterus
chorion cancer JAR, embryo transversal cancer RD, ovarian
cancer HO-8910 cell lines and fibroblast cell line NIH-3T3
were purchased from Shanghai Institutes for Biological Sciences
(Shanghai, China). HUVECs were obtained from the
American Type Culture Collection (ATCC, Rockville, MD).
2.2. Cell culture
The four human cancer cell lines: Hela, JAR, RD, HO-
8910 and NIH-3T3 cells were cultured in RPMI 1640
medium supplemented with 10% fetal calf serum and antibiotics
(100 IU ml−1 penicillin and 100
gml−1 streptomycin),
at 37 ◦C, 5% CO2 in air. HUVECs were grown
in DMEM medium with 10% FCS, 10 ng ml−1 VEGF and
antibiotics. HUVECs were used within 10 passages. Human
endometrium cells were isolated from the uterus of
misbirth woman by 0.05% trypsin digestion and cultured
in DMEM medium with 15% FCS. Cells were used within
seven passages. Human endometrium cells were cultured
and checked by the technologist of Shanghai Institutes for
Biological Sciences.
2.3. Growth assay of various types of cells
Four cancer cells, NIH-3T3 cells and endometrium cells
were plated in 24-well plates at a density of 1×104 cells per
well. After 24 h of culture in the normal growth medium,
cells were exposed to graded concentrations of ART or dihydroartemisinin
for 48 h. Cells were then incubated with
5mgml−1 MTT solution for 4 h. One hundred microliter
of 10% sodium dodecyl sulfate solution was added to the
culture. Absorbance at 570 nm was determined by using
an ELISA reader (Bio-Tek instruments, Inc., USA). By the
MTT method, cell numbers were obtained as absorbance
values. The results were expressed as IC50 values (50%
inhibitory concentration).
2.4. Growth inhibition assay of HUVECs
HUVECs were seeded at a density of 1 × 104 cells per
well into 24-well plates. After 24 h incubation at 37 ◦C in a
5% CO2 incubator, ART or dihydroartemisinin at different
concentrations were added to the wells and the cells were
further cultured for 48 h. The number of cells was counted
with a coulter counter. Cell viability was evaluated by the
trypan blue exclusion test.
2.5. HUVEC migration assay
5 × 104 HUVECs per well were seeded into 24-well
plates and grown to confluence. The ‘scratch wound’ in
the confluence monolayers was made using a razor blade,
then each well was rinsed with PBS and 10% FBS–DMEM
medium containing ART or dihydroartemisinin were added.
The plates were incubated at 37 oC, 5% CO2 in air for 24 h.
The number of cells that had migrated from the edge of
the wound in each 250
m × 500
m area of 10 randomly
chosen fields was counted. Results were expressed as the
average number of cells per field.
2.6. Cell microvessel formation assay
HUVEC differentiation was evaluated by using a tube
formation method as described previously [13,14] with minor
modifications. An 8:1:1 volume of 3mgml−1 Type I
collagen, DMEM (10×), 0.1M NaOH + 0.2M HEPES +
0.26M Na2CO3 was made and poured into 24-well plates
with 750
l per well at 4 ◦C. After a collagen gel formed
by incubating at 37 ◦C for 1 h, 1 × 104 HUVECs per well
were seeded on the collagen-coated wells and incubated for
24 h. Subsequently, 10% FBS–DMEM supplemented with
10 ng ml−1 VEGF containing ART or dihydroartemisinin
were added into the wells. After incubation for 3 days, microvessel
formation was observed using a light microscopy
and photographed. The total lengths of the tubular structures
in three randomly chosen microscopic fields per well were
measured by making use of a curvimeter in the microscope
(Olympus, Tokyo, Japan).
2.7. Data analysis
All values are expressed as the mean±S.D. and the significant
levels between two groups were assessed by Student’s
t-test. P values less than 0.05 were considered to be statistically
significant.
3. Results
3.1. Effect of ART and dihydroartemisinin on the growth
of various types of cells
Both ART and dihydroartemisinin inhibited the growth
of the four cancer cell lines in a concentration-dependent
H.-H. Chen et al. / Pharmacological Research 48 (2003) 231–236 233
Table 1
Inhibition (IC50) of four cancer cell lines by ART and dihydroartemisinin
Substance Cell line, IC50 (
M)
Hela JAR RD HO-8910
ART 38.6 ± 4.3 40.4 ± 5.8 15.4 ± 1.0 49.7 ± 6.9
Dihydroartemisinin 15.7 ± 3.7 24.5 ± 5.3 8.5 ± 1.1 32.9 ± 4.7
Various cells were cultured with ART or dihydroartemisinin for 48 h and
cell growth was assessed by the MTT colorimetric method. Results of
experiments in triplicate are expressed as the IC50 values that suggest
the inhibitory activity of ART and dihydroartemisinin against four cancer
cell lines.
manner by the MTT assay. Treatment with ART and dihydroartemisinin
at concentrations greater than 5
M for 2
days reduced the cell growth of all four lines at different
levels. RD cell line was the most sensitive to ART and dihydroartemisinin
in this test panel, and can be inhibited 89.7%
or 94.5% by 120
M ART or 120
M dihydroartemisinin,
respectively. The other cancer cell lines can be inhibited
above 80% by 120
M ART or 120
M dihydroartemisinin
(data not shown). The IC50 of the four cancer cell lines
by ART and dihydroartemisinin was shown at Table 1.
We showed that dihydroartemisinin was more effective in
inhibiting all the four cell lines growth than ART.
We also tested the effects of ART and dihydroartemisinin
on the proliferation of the normal control cells. The IC50 values
for NIH-3T3 cells and human endometrium cells were
105.77
M or 69.56
M for ART or dihydroartemisinin
and 139.4
M or 88.02
M for ART or dihydroartemisinin,
respectively.
3.2. Effects of ART and dihydroartemisinin on
proliferation of HUVECs
Effects of ART and dihydroartemisinin on proliferation
of HUVECs were observed (Fig. 1). Cell proliferation was
Fig. 1. Quantification of inhibitory effects of ART and dihydroartemisinin
on HUVECs. HUVECs were plated in 24-well plates, allowed to attach
for 24 h and then treated with different concentrations of ART or dihydroartemisinin
for 2 days. Cell proliferation was determined by cell
counting. Data represent the average (±S.D.) of three experiments. Symbols
indicate ART ( ) and dihydroartemisinin ( ). (*) P < 0.05; (**)
P < 0.01, compared to control.
inhibited in a concentration-dependent manner. At every
concentration >0.5
M, the groups of treatment with ART
and dihydroartemisinin were significantly different when
compared with each other (P < 0.05). Dihydroartemisinin
was more effective than ART in inhibiting the cell growth.
At the highest concentration of 50
M ART and dihydroartemisinin
had inhibition rates of about 40 and 50%,
respectively.
The above results show that the IC50 values for HUVEC
and four human cancer cell lines were all lower than those for
fibroblast cells and human endometrium cells, indicating that
the growth inhibition activity of ART and dihydroartemisinin
against HUVEC and the four cancer cell lines was stronger
than fibroblast cells and human endometrium cells.
3.3. Effects of ART and dihydroartemisinin on migration
of HUVECs
On HUVECs, either ART or dihydroartemisinin induced
a dose-dependent decrease in cell migration (Figs. 2 and 3).
Compared to the inhibition of cell growth, the effect was
evident from lower concentrations. ART and dihydroartemisinin
suppressed cell migration slightly at a concentration
of 0.5
M and inhibited it completely at 50
M. Dihydroartemisinin
was more effective than ART (P < 0.01).
3.4. Effects of ART and dihydroartemisinin on HUVEC
tube formation
We tested the effects of ART and dihydroartemisinin on
HUVEC tube formation in vitro. Tubulogenesis was induced
in vascular ECs by seeding them on the surface of
the collagen (Type I) gel for 24 h. Fig. 4 shows the branching
vessel-like structures formed by HUVECs. When ART
or dihydroartemisinin was added to the culture, there was a
Fig. 2. Quantitative inhibition of HUVECs by ART and dihydroartemisinin.
Confluent cultures of HUVECs were wounded with a razor blade.
The cells were incubated with ART or dihydroartemisinin at different
concentrations for 24 h. The numbers of cells migrated from the edge
of the wound within each 125
m × 500
m area were counted. Data
represent the average (±S.D.) (n = 3). Symbols indicate ART ( ) and
dihydroartemisinin ( ). (*) P < 0.05; (**) P < 0.01, compared to control.
234 H.-H. Chen et al. / Pharmacological Research 48 (2003) 231–236
Fig. 3. Effect of dihydroartemisinin on HUVECs migration. Microscopic
morphology (200×) of HUVECs treated as in Fig. 2: (a) control; (b)
2.5
M dihydroartemisinin; (c) 50
M dihydroartemisinin.
decrease in both the number and length of tube formation in
a dose-dependent manner (Fig. 5). There was approximately
70 or 90% reduction in the total tube length per field following
50
M ART or dihydroartemisinin treatment for 48 h,
respectively. The inhibitory activity of dihydroartemisinin
is also greater than that of ART (P < 0.01).
4. Discussion
Although some studies have shown that the anti-malarial
ART and dihydroartemisinin were active against many
cancer cell lines in vitro [5,6,15], their effects on these
four cancer cell lines Hela, JAR, RD and HO-8910 were
not reported. In this investigation, we examined ART and
dihydroartemisinin’s anti-tumor activity on the above four
cancer cell lines to extend the anti-tumor spectrum of the
two drugs. The IC50 values of these four cell lines were
different according to their different sensitivities towards
ART and dihydroartemisinin. Ovarian cancer line showed
Fig. 4. Effect of dihydroartemisinin on HUVEC tube formation. Microscopic
morphology (200×) of HUVECs treated as in Fig. 5: (a) control;
(b) 12.5
M dihydroartemisinin; (c) 50
M dihydroartemisinin.
Fig. 5. Dose-dependent inhibition of HUVEC tube formation by ART and
dihydroartemisinin. HUVECs were plated in a three-dimensional culture
system on collagen gels and then treated by ART or dihydroartemisinin
at different concentrations for 2 days. Total length of tube formation
per field was measured and results were expressed as percent of control
(average ± S.D.) (n = 3). Symbols indicate ART ( ) and dihydroartemisinin
( ). (*) P < 0.05; (**) P < 0.01, compared to control.
H.-H. Chen et al. / Pharmacological Research 48 (2003) 231–236 235
the highest IC50 values indicating the lowest sensitivity to
both ART and dihydroartemisinin in this test panel. While,
either ART or dihydroartemisinin was most active against
embryo transversal cancer cell line RD. Compared to ART,
dihydroartemisinin had greater anti-tumor activity in vitro.
Angiogenesis plays a vital role in tumor growth, intrasavation,
metastatic spread [10,11]. Inhibition of angiogenesis
provides a good chance of preventing cancer from becoming
malignant [16,17]. Angiogenesis is composed of several
process dissociations of pericytes from preexisting vessel,
digestion of extracellular matrix with proteases growth, migration
and invasion of ECs, tube formation, then finally remodeling
occurs. Among these processes, growth, migration
and tube formation of ECs are essential for angiogenesis.
This motivates us to determine anti-angiogenic activities of
ART and dihydroartemisinin by inhibiting HUVECs growth,
migration and tube formation. Our data showed that the inhibition
of HUVECs growth of dihydroartemisinin occurred
at higher concentration than the concentrations needed to
inhibit cell migration and tube formation. It was expected
that the suppression of angiogenesis by dihydroartemisinin
might not be induced only by inhibiting ECs proliferation.
The mechanism of such effect should be studied further.
In the present investigation of anti-angiogenic activity, results
suggested that dihydroartemisinin and ART were two
potent inhibitors. It was known that dihydroartemisinin
was the main product of artemisinin and its derivatives
including ART by metabolization of human bodies. This
information together with our results indicated ART and
other artemisinin drugs might continue to be active or even
more against cancer after metabolization in human bodies.
The mechanism of inhibition of ART and dihydroartemisinin
on tumor growth is not studied exhaustively. It is
well known that the artemisinin and its derivative molecules
contain an endoperoxide bridge that reacts with a ferrous
iron atom to form free radicals which contributes to their
anti-malarial activity [18,19]. However, whether the formation
of radical molecules and/or reactive oxygen species
of artemisinin drugs contributes to their anti-tumor activity
is not completely proved. Moreover, it is not known
whether genetic pathways are involved in cancer cells and
to which extent they vary in different derivatives [20,21].
Singh and Lai have shown that dihydroartemisinin and
ART are selectively toxic to human cancer cells and with
relatively low toxicity on normal human cells [22,23]. It is
also reported that artemisinin derivatives are active against
many drug-resistant cancer cell lines, such as small-cell
lung cancer (SCLC) [24]. Compared to normal cells, cancer
cells contain higher rates of iron intake correlated with their
high transferrin receptor concentration. So, cancer cells including
drug-resistant cancer cells are more susceptible to
artemisinin drugs under conditions of high iron availability
[25,26].
Although we suggested the inhibitory effects of ART
and dihydroartemisinin on angiogenesis in vitro, the mechanism
of inhibition is still not clear at the present time and
further studies are needed to gain a full understanding of
the anti-angiogenic activity in vivo.
Since many identified tumor and angiogenesis inhibitors
have problems concerning their therapeutic applications
because of their excessive toxicity and limited efficacy. The
anti-tumor and anti-angiogenic efficacy together with the
known low and selective toxicity make it possible that ART
and dihydroartemisinin may be promising novel candidates
for cancer chemotherapy.
Acknowledgements
This work was supported in part by a Grant-in-Aid for
new drug research from National Key Laboratory of Chinese
Academy of Sciences and by funds for Scientific Research
from Zhejiang University.
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Artemisinin

Systematic (IUPAC) name
(3R,5aS,6R,8aS,9R,12S,12aR)- octahydro-3,6,9-trimethyl-3,12- epoxy-12H-pyrano[4,3-j]- 1,2-benzodioxepin-10(3H)-one
Identifiers
CAS number	63968-64-9
ATC code	P01BE01
PubChem	CID 68827
ChemSpider	62060 Y
KEGG	D02481
Chemical data
Formula	C15H22O5
Mol. mass	282.332 g/mol
SMILES	eMolecules & PubChem
InChI[show] InChI=1S/C15H22O5/c1-8-4-5-11-9(2)12(16)17-13-15(11)10(8)6-7-14(3,18-13)19-20-15/h8-11,13H,4-7H2,1-3H3/t8-,9-,10+,11+,13-,14-,15-/m1/s1 Y Key: BLUAFEHZUWYNDE-NNWCWBAJSA-N Y
Synonyms	Artemisinine, Qinghaosu
Physical data
Density	1.24 ± 0.1 g/cm³
Melt. point	152–157 °C (306–315 °F)
Therapeutic considerations
Pregnancy cat.	?
Legal status	?
Routes	Oral
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Artemisinin (pronounced /ɑrtɨˈmɪsɨnɨn/), also known as qinghaosu, and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria[1]. Treatments containing an artemisinin derivative (artemisinin-combination therapies, ACTs) are now standard treatment worldwide for falciparum malaria. The starting compound, artemisinin (a sesquiterpene lactone), is isolated from the plant Artemisia annua, a herb described in Chinese traditional medicine, though it is usually chemically modified and combined with other medications.

Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization as there have been signs that malarial parasites are developing resistance to the drug. Combination therapies that include artemisinin are the preferred treatment for malaria and are both effective and well tolerated in patients. The drug is also increasingly being used in vivax malaria[2] as well as being a topic of research in cancer treatment.

Contents [hide] 1 History 2 Artemisinin derivatives 2.1 Chemically modified analogues 2.2 Purely synthetic analogues 3 Indications 3.1 Malaria 3.2 Cancer treatment 3.3 Helminth parasites 4 Resistance 5 Adverse effects 6 Mechanism of action 7 Dosing 8 Synthesis 9 Legal Status 10 References 11 External links

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[edit] History

Artemisia has been used by Chinese herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC, in the "Fifty-two Prescriptions" unearthed from the Mawangdui Han Dynasty Tombs. Its antimalarial application was first described in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of the fourth century by Ge Hong.

In the 1960s a research program, under the name Project 523, was set up by the Chinese army to find an adequate treatment for malaria. In 1972, in the course of this research, Tu Youyou (Chinese: 屠呦呦)[3] discovered artemisinin in the leaves of Artemisia annua (annual wormwood). The drug is named qinghaosu (Chinese: 青蒿素) in Chinese. It was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional Chinese medicines for treating malaria. It was the only one that was effective, but it was found that it cleared malaria parasites from their bodies faster than any other drug in history. Artemisia annua is a common herb and has been found in many parts of the world, including along the Potomac River, in Washington, D.C. Images of the original scientific papers are available online[4] and a book, Zhang Jianfang, "Late Report – Record of Project 523 and the Research and Development of Qinghaosu", Yangcheng Evening News Publisher 2007(張劍方. 遲到的報告五二三項目與青蒿素研發紀實. 羊城晚報出版社, 2007),[5] was published in 2006, which records the history of the discovery.

It remained largely unknown to the rest of the world for about ten years, until results were published in the Chinese Medical Journal[6]. The report was met with skepticism at first, partly because the chemical structure of artemisinin, particularly the peroxide, appeared to be too unstable to be a viable drug.

[edit] Artemisinin derivatives

Because artemisinin itself has physical properties such as poor bioavailability that limit its effectiveness, semi-synthetic derivatives of artemisinin, including artemether and artesunate, have been developed.

[edit] Chemically modified analogues

There are a number of derivatives and analogues within the artemisinin family:

• Artesunate (water-soluble: for oral, rectal, intramuscular, or intravenous use)
• Artemether (lipid-soluble: for oral, rectal or intramuscular use)
• Dihydroartemisinin
• Artelinic acid
• Artenimol
• Artemotil

There are also simplified analogs in preclinical research.[7]

[edit] Purely synthetic analogues

To counter the present shortage in leaves of Artemisia annua, researchers have been searching for a way to develop artemisinin artificially in the laboratory. A 2006 paper in Nature[8] presented a genetically engineered yeast that can synthesize a precursor called artemisinic acid which can be chemically converted to artemisinin.

A synthetic compound with a similar trioxolane structure (OZ-277, also known as RBx11160 or arterolane) [9] showed promise in in vitro testing. However in phase II testing (in patients with malaria) the drug did not prove as effective as hoped[10]. A combination with piperaquine remains in development.

[edit] Indications

[edit] Malaria

Artemisinins can be used alone, but this leads to a high rate of recrudescence (return of parasites) and other drugs are required to clear the body of all parasites and prevent recurrence. The World Health Organization is pressuring manufacturers to stop making the uncompounded drug available to the medical community at large, aware of the catastrophe that would result if the malaria parasite developed resistance to artemisinins.[11]

The World Health Organisation has recommended that artemisinin combination therapies (ACT) be first-line therapy for P. falciparum malaria worldwide[12]. Fixed-dose combinations work as the partner drug is present to eradicate the last parasites while the artemisinin component removes the majority at the start of the treatment[13].

A large number of fixed-dose ACTs are now available containing an artemisinin component and a partner drug which has a long half-life, such as mefloquine (ASMQ[14]), lumefantrine (Coartem), amodiaquine (ASAQ), piperaquine (Duo-Cotecxin) and antifolates (Ariplus). Increasingly these combinations are being made to GMP standard. A separate issue concerns the quality of some artemisinin-containing products being sold in Africa and South-East Asia[15][16].

Artemisinins are not used for malaria prophylaxis (prevention) because of the extremely short activity (half-life) of the drug. To be effective, it would have to be administered multiple times each day.

[edit] Cancer treatment

Artemisinin is undergoing early research and testing for the treatment of cancer, primarily by researchers at the University of Washington.[17][18] Chinese scientists have shown artemisinin has significant anticancer effects against human hepatoma cells.[19] Artemisinin has a peroxide lactone group in its structure, and it is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species. It has been shown to reduce angiogenesis and the expression of vascular endothelial growth factor in some tissue cultures.

[edit] Helminth parasites

Serendipitous discovery was made in China while searching for novel anthelmintics for schistosomiasis. Artemisinin was effective against schistosomes, the human blood flukes, which are the second most prevalent parasitic infections, after malaria. Artemisinin and its derivatives are all potent anthelmintics.[20] They are later found to possess a broad spectrum of activity against a wide range of trematodes including Schistosoma japonicum, S. mansoni, S. haematobium, Clonorchis sinensis, Fasciola hepatica and Opisthorchis viverrini. Clinical trials are also successfully conducted in Africa among patients with schistosomiasis.[21] A randomized, double-blind placebo-controlled trial also revealed the efficacy against schistosome infection in Côte d'Ivoire[22] and China.[23]

[edit] Resistance

A study published in 2008 by Noedl and colleagues in the New England Journal of Medicine suggests a consensus among researchers that artemisinin is losing its potency in Cambodia and increased efforts are required to prevent drug-resistant malaria from spreading across the globe.[24]. These findings were subsequently supported by a detailed study from Western Cambodia[25].

[edit] Adverse effects

Artemisinins are generally well tolerated at the doses used to treat malaria.[26] The side effects from the artemisinin class of medications are similar to the symptoms of malaria: nausea, vomiting, anorexia, and dizziness. Mild blood abnormalities have also been noted. A rare but serious adverse effect is allergic reaction.[26][27] One case of significant liver inflammation has been reported in association with prolonged use of a relatively high-dose of artemisinin for an unclear reason (the patient did not have malaria).[28] The drugs that are used in combination therapies can contribute to the adverse effects that are experienced by those undergoing treatment. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives tend to be higher.[29]

[edit] Mechanism of action

There is no consensus regarding the mechanism through which artemisinin derivatives kill the parasites[30]. Their site of action within the parasite also remains controversial.

At the chemical level, one theory states that when the parasite that causes malaria infects a red blood cell, it consumes hemoglobin within its digestive vacuole, liberating free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death[31].

Numerous studies have investigated the type of damage that oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin.[32] These observations were supported by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin and inhibition of hemozoin formation by malaria parasites. Electron microscopic evidence linking artemisinin action to the parasite's digestive vacuole has been obtained showing that the digestive vacuole membrane suffers damage soon after parasites are exposed to artemisinin.[33]. This would also be consistent with data showing that the digestive vacuole is already established by the mid-ring stage of the parasite's blood cycle [34], a stage that is sensitive to artemisinins but not other antimalarials.

A previously highly cited theory that the parasite's SERCA pump (PfATP6) was a key target of artemisinins now appears highly questionable. Artemisinins do not inhibit this protein when it is expressed in yeast[35] and transfection studies show no significant effect of PfATP6 genotype on artemisinin phenotype[36]. Although a single field study identified a mutation in PfATP6 that was associated with resistance to artemether[37], this mutation has not achieved a meaningful prevalence in any location and a phenotypic association has not been reported elsewhere. There is no evidence to suggest a role for PfSERCA in the artemisinin resistance that appears to be emerging in Cambodia[24][25].

A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane.[38]

[edit] Dosing

Artemisinin and its derivatives have half-lives in the order of a few hours and therefore require at least daily dosing, usually for three days. For example the WHO approved adult dose of co-artemether (artemether-lumefantrine) is 4 tablets at 0, 8, 24, 36, 48 and 60 hours (six doses).[39][40] This regimen has been proven to be superior to regimens based on amodiaquine.[41]

Artemesinin is not soluble in water and therefore Artemisia annua tea was postulated not to contain pharmacologically significant amounts of artemesinin.[42] However, this conclusion was rebuked by several experts who stated that hot water (85 oC), and not boiling water, should be used to prepare the tea. Although Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination therapies) more clinical studies on artemisia tea preparation have been suggested.[43]

[edit] Synthesis

In 2006 a team from UC Berkeley published an article claiming that they had engineered Saccharomyces cerevisiae yeast that can produce the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and turned into a drug that they claim will cost roughly 0.25 cents per dose. Details of the formation of artemisinic acid involves a mevalonate pathway, expression of amorphadiene synthase, a novel cytochrome P450 monooxygenase (CYP71AV1) and its redox partner from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.[8] Amyris Biotechnologies is collaborating with UC Berkeley and the Institute for One World Health to further develop this technology [44]

Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 m and which produces 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical organisation, Médecins sans frontières (MSF), ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea. Cultivation of this crop may well prove a valuable niche market for Africa, given the strong demand for the plant from pharmaceutical laboratories.

The biosynthesis of artemisinin is expected to involve the mevalonate pathway (MVA) and the cyclization of FDP (farnesyl diphosphate). Although it is not clear whether the DXP (deoxyxylulose phosphate)pathway can also contribute 5-carbon precursors (IPP or/and DMAPP), as occurs in other sesquiterpene biosynthetic system. The routes from artemisinic alcohol to artemisinin remain controversial and they differ mainly in when the reduction step takes place. Both routes suggested dihydroartemisinic acid as the final precursor to artemisinin. Dihydroartemisinic acid then undergoes photoxidation to produce dihydroartemisinic acid hydroperoxide. Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation furnish the biosynthesis of artemisinin.

Figure 1. Biosynthesis of Artemisinin.

The total synthesis of artemisinin can also be performed using basic organic reagents. In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which as converted to methoxymethyl ether (3). The ether was hydroborated and then underwent oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which would be oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li, NH3) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (12). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.[45]

Furthermore, a research group from the Philippines have published a work on the extraction of artemisinin from its plant source, Artemisia annua. Their work produced a synthetic polymer that was imprinted with artemisinin and showed a selective recognition to the said compound.

[edit] Legal Status

For many years, access to the purified drug and the plant it was extracted from were restricted by the Chinese government. It was not until the late 1970s and early 80s that news of the discovery reached scientists outside China. The World Health Organisation (WHO) tried to contact Chinese scientists and officials to find out more, but drew a blank. Dr Ying Lee, one of the scientists involved in the research into artemisinin, said the Chinese distrusted the West. The Chinese suspected the West just wanted to exploit the drug and sell it around the world slightly altered and repatented. The fact that there were several Americans on the WHO's steering board on malaria and that some were from the military did not help clear the distrust. It can be noted Americans had just invested a lot into mefloquine, an analogue of chloroquine.

[edit] References

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[edit] External links

Look up artemisinin in Wiktionary, the free dictionary.

• History, Aetiology, Pathophysiology, Clinical Features, Diagnosis, Treatment, Complications And Control Of Malaria: Artemisinin Derivatives
• Design and synthesis of antimalarial endoperoxides
• van Vugt M, Looareesuwan S, Wilairatana P, et al. (2000). "Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria". Trans. R. Soc. Trop. Med. Hyg. 94 (5): 545–8. doi:10.1016/S0035-9203(00)90082-8. PMID 11132386. 
• Daviss B (2005). "Malaria, Science, and Social Responsibility: Nonprofit drug-development partnership seeks to cure the ills of developing nations". The Scientist 19 (6): 42. http://www.the-scientist.com/2005/3/28/42/1. 
• Research on the use of artemisinin for cancer treatment
• Ferreira, J.F. (2004). "Artemisia Annua L.: the Hope Against Malaria and Cancer". Proceedings of the 2nd Annual Symposium, Appalachian Opportunities, Medicinal and Aromatic Plants: Production, Business & Applications. Mountain State University/USDA, ARS, Appalachian Farming Systems Research Center. pp. 56–61. http://www.ars.usda.gov/research/publications/Publications.htm?seq_no_115=168984. 
• Artemisinin — Researchers blend folk treatment, high tech for promising anti-cancer compound
• BBC Horizon documentary about artemisinin
• Artemisinin: From Malaria to Cancer Treatment, by Robert Jay Rowen, MD Editor-in-Chief, Second Opinion
• Artemisia Annua, by Memorial-Sloan Kettering Cancer Center
• Use of Artemisinin for Cancer Treatment and Bacterial Infection, Henry Lai, Ph.D., University of Washington (streaming video, Spring 2005)
• WHO calls for an immediate halt to provision of single-drug artemisinin malaria pills: New malaria treatment guidelines issued by WHO
• Assured Artemisinin Supply System, support the global production of sufficient Artemisia/artemisinin to meet the expanded needs

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