ARTEMISININ-080602
**********************************************************
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 [PubMed - indexed for MEDLINE
**********************************************************
Wormwood is the basis for a cancer-fighting pill
By Environmental News Network
Wednesday, November 28, 2001
A nontoxic pill that could be taken on an outpatient basis to combat breast cancer
or leukemia sounds like a fantasy, but the treatment is becoming a reality due to
the investigation of a University of Washington research team into an ancient
Chinese remedy for malaria.
Two bioengineering research professors at the University of Washington have
rediscovered wormwood as a promising potential treatment for cancer among the
ancient arts of Chinese folk medicine.
Research professor Henry Lai and assistant research professor Narendra Singh
have exploited the chemical properties of a wormwood derivative to target breast
cancer cells with surprisingly effective results. A study in the latest issue of the
journal Life Sciences describes how the derivative killed virtually all human breast
cancer cells exposed to it within 16 hours.
"Not only does it appear to be effective, but it's very selective," Lai said. "It's
highly toxic to the cancer cells but has a marginal impact on normal breast cells."
Environmental risk factors for cancer are many. Lifetime exposure to the female
hormone estrogen and estrogen-mimicking chemicals such as some pesticides
1
and herbicides has been linked to an increase in breast cancer risk. In 1991, the
International Agency for Research on Cancer classified the pesticide DDT as a
possible human carcinogen, and the U.S. Environmental Protection Agency (EPA)
has classified DDT as a probable human carcinogen.
The manufacture of PCBs, the oily liquids or solids used as coolants and
insulators, was stopped in the United States in 1977 because of concerns that
exposure increases the risk of cancers, but PCBs are still found in the
environment.
Most Americans are exposed every day to air toxins emitted by motor vehicles,
substances that the EPA says have been proven to cause cancer in humans.
"Benzene, says the EPA, "is a known human carcinogen, while formaldehyde;
acetaldehyde; 1,3-butadiene; and diesel particulate matter are probable human
carcinogens." The EPA has now classified 1,3-butadiene, a gas used commercially
in the production of resins and plastics, as a known human carcinogen.
The use of the bitter herb wormwood is nothing new. Used for centuries to rid the
body of worms, it is also an ingredient in the alcoholic beverage absinthe, now
banned in most countries.
Artemisinin, the compound that Lai and Singh have found to fight cancers, isn't
new either. It was extracted from the plant Artemesia annua L., commonly known
as wormwood, thousands of years ago by the Chinese, who used it to combat the
mosquito-borne disease malaria. The treatment with artemisinin was lost over
time but rediscovered during an archaeological dig in the 1970s that unearthed
recipes for ancient medical remedies.
Now widely used in Asia and Africa to fight malaria, artemisinin reacts with the
high iron concentrations found in the malaria parasite. When artemisinin comes
into contact with iron, a chemical reaction ensues, spawning charged atoms that
chemists call free radicals. The free radicals attack cell membranes, breaking
them apart and killing the single-cell parasite.
About seven years ago, Lai began to hypothesize that the process might work
with cancer, too.
"Cancer cells need a lot of iron to replicate DNA when they divide," Lai explained.
"As a result, cancer cells have much higher iron concentrations than normal cells.
When we began to understand how artemisinin worked, I started wondering if we
could use that knowledge to target cancer cells."
Lai devised a potential method and began to look for funding, obtaining a grant
from the Breast Cancer Fund in San Francisco. Meanwhile, the UW patented his
idea.
The thrust of the idea, according to Lai and Singh, was to pump up the cancer
cells with maximum iron concentrations, then introduce artemisinin to selectively
kill the cancer.
2
In the current study, after eight hours, just 25 percent of the cancer cells
remained. By the time 16 hours had passed, nearly all the cells were dead.
An earlier study involving leukemia cells yielded even more impressive results.
The cancer cells were eliminated within eight hours. A possible explanation might
be the level of iron in the leukemia cells. "They have one of the highest iron
concentrations among cancer cells," Lai explained. "Leukemia cells can have more
than 1,000 times the concentration of iron that normal cells have."
The next step, according to Lai, is animal testing. Limited tests have been done in
that area. In an earlier study, a dog with bone cancer so severe it couldn't walk
made a complete recovery in five days after receiving the treatment. But more
rigorous testing is needed.
If the process lives up to its early promise, it could revolutionize the way some
cancers are approached, Lai said. The goal would be a treatment that could be
taken orally on an outpatient basis.
"That would be very easy, and this could make that possible," Lai said. "The cost
is another plus: At $2 a dose, it's very cheap. And with the millions of people who
have already taken artemisinin for malaria, we have a track record showing that
it's safe."
Whatever happens, Lai said, a portion of the credit will have to go to unknown
medical practitioners, long gone now. "The fascinating thing is that this was
something the Chinese used thousands of years ago," he said. "We simply found
a different application
Wednesday, 28 November, 2001, 00:56 GMT
Chinese remedy 'may fight cancer'
An ancient Chinese folk remedy may hold the key to a non-toxic treatment for
cancer.
Researchers from the University of Washington have discovered breast cancer cells can be effectively
targeted, using a chemical derived from the wormwood plant called artemisinin.
The derivative killed virtually all the breast cancer cells exposed to it within 16 hours.
The US team hopes eventually the treatment will made available in pill form on an out-patient basis.
Researcher Professor Henry Lai said: "Not only does it appear to be effective, but it's very selective.
"It's highly toxic to the cancer cells, but has a marginal impact on normal breast cells."
Artemisinin was extracted from wormwood thousands of years ago by the Chinese, who used it to
combat malaria.
However, the treatment was lost over time. Artemisinin was rediscovered during an archaeological dig
in the 1970s that unearthed recipes for ancient medical remedies, and has become widely used in
modern Asia and Africa to fight the mosquito-borne disease.
The compound helps control malaria because it reacts with the high iron concentrations found in the
malaria parasite. This reaction generates charged atoms called free radicals that kill the infected cells
by ripping open their protective membranes.
Professor Lai found that the same principle holds good for cancer cells which need a lot more iron than
normal cells to help them divide rapidly.
3
His team pumped up the cancer cells with maximum iron concentrations and then exposed them to
artemisinin.
After eight hours, just 25% of the cancer cells remained. By the time 16 hours had passed, nearly all the
cells were dead.
Leukaemia
An earlier study involving leukaemia cells yielded even more impressive results - this could be because
leukaemia cells have one of the highest iron concentrations among cancer cells.
The researchers now plan to carry out tests on animals.
Professor Lai said a drug treatment based on artemisinin would be very cheap.
"With the millions of people who have already taken artemisinin for malaria, we have a track record
showing that it's safe.
"The fascinating thing is that this was something the Chinese used thousands of years ago. We simply
found a different application."
Dr Richard Sullivan, director of clinical trials for the Cancer Research Campaign, said the research was
"very interesting".
"When I hear about a Chinese herbal remedy I worry about it slightly, because often they are based on
very little scientific evidence, but this has a strong underlying scientific and biological rational to it.
"We tend to concentrate on designer drugs, rather than looking at nature, but perhaps we should
remember that nature has had millions of years to come up with solutions."
The research is published in the journal Life Sciences.
J Nat Prod 2002 Feb;65(2):184-8
Deoxyartemisinin derivatives from photooxygenation of anhydrodeoxydihydroartemisinin and
their cytotoxic evaluation.
Galal AM, Ross SA, ElSohly MA, ElSohly HN, El-Feraly FS, Ahmed MS, McPhail AT.
National Center for Natural Products Research, University of Mississippi, 38677, USA.
amgalalv@yahoo.com
Photooxygenation of anhydrodeoxydihydroartemisinin (4) followed by chromatographic separation of
the reaction mixture yielded the new compounds alpha- (5) and beta-hydroperoxydeoxyartemisitene (8)
and the formate ester 7, together with two previously reported compounds, 6 and 9. Reduction of 5
using polymer-bound triphenylphosphine afforded the new compound dihydrodeoxyartemisitene (10).
Treatment of 10 with a catalytic amount of BF(3)-OEt(2) yielded the C(2)-symmetrical dimer
bis(dihydrodeoxyartemisitene) ether (11) and two new compounds, dihydrodeoxyartemisitene methyl
ether (12) and the dimer 13, as minor products. Dehydroacetoxylation of 5 using acetic anhydride in
pyridine afforded deoxyartemisitene (14). The identities of the new compounds (5, 7, 8, 10-14) were
deduced from their spectral data and by chemical derivatization. The stereochemistry of dimer 11 was
defined on the basis of X-ray crystallographic analysis. All compounds were evaluated in vitro in the
National Cancer Institute drug-screening program consisting of 60 human cancer cell lines derived
from nine different tissues. Of the compounds tested, deoxyartemisitene (14) demonstrated significant
cytotoxicity against a number of human cancer cell lines.
PMID: 11858753 [PubMed - indexed for MEDLINE
**********************************************************
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.
4
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. GST P1-1 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. The IC(50) values obtained for 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 [PubMed - indexed for MEDLINE]
**********************************************************
Eur J Med Chem 2001 May;36(5):469-79
Synthesis and cytotoxicity of artemisinin derivatives containing cyanoarylmethyl group.
Wu JM, Shan F, Wu GS, Li Y, Ding J, Xiao D, Han JX, Atassi G, Leonce S, Caignard DH,
Renard P.
Department of Synthetic Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, Shanghai 200031, China.
A series of 12alpha-deoxoartemisinyl cyanoarylmethyl dicarboxylates (4a-4o), dicarboxylic acids
12alpha-deoxoartemisinyl ester cyanoarylmethyl amide (5a-5k), and dicarboxylic acids 12alphadeoxoartemisinyl ester N-methylcyanoarylmethyl amide (6a-6l), showing moderate cytotoxicity against
P388 and L1210 cells were prepared. They induced the significant accumulation of L1210 and P388
cells in the G1 phase of the cell cycle. This mechanism of action was quite different from that of the
majority of cytotoxic compounds used in the chemotherapy of cancer. Compound 4b possessed better
cytotoxicity than the other compounds.
PMID: 11451535 [PubMed - indexed for MEDLINE]
**********************************************************
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.
5
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 antitumor 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 wildtype 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 [PubMed - indexed for MEDLINE]
**********************************************************
Biochem Biophys Res Commun 2000 Aug 2;274(2):359-69
NMR studies on novel antitumor drug candidates, deoxoartemisinin and
carboxypropyldeoxoartemisinin.
Lee CH, Hong H, Shin J, Jung M, Shin I, Yoon J, Lee W.
Department of Biochemistry, College of Science, Yonsei University, Seoul, Korea.
Artemisinin and its derivatives, which have been known as antimalarial drugs, have also demonstrated
their cytotoxicity against tumor cells. It has been proposed that antitumor activity depends on the
lipophilicity of functional group on artemisinin derivatives. Solution structures of two artemisinin
derivatives as antitumor drug candidates, deoxoartemisinin and carboxypropyldeoxoartemisinin, were
determined by NMR spectroscopy to elucidate structure-activity relationship. According to biological
assay, antitumor efficiencies are not dependent upon lipophilicity. Instead, these compounds
demonstrated their distinctive structural features of boat/chair conformation and capability to interact
with receptors, as they have different efficiencies on antitumor activity. Especially, carboxypropyl
moiety or carbonyl moiety in artemisinin derivatives influences the conformation and stability of ring
structure. Although the detailed mechanism of antitumor activity by artemisinin derivatives has not
been addressed, we suggest that antitumor activity is not determined only with lipophilicity and that
artemisinin derivatives have specific target proteins in each type of cancer. Copyright 2000 Academic
Press.
PMID: 10913344 [PubMed - indexed for MEDLINE]
**********************************************************
6
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, elFeraly 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 CFUGM 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 CFUGM 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 [PubMed - indexed for MEDLINE]
**********************************************************
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 [PubMed - indexed for MEDLINE]
**********************************************************
Zhongguo Yao Li Xue Bao 1992 Nov;13(6):541-3
Erratum in:
7

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 [PubMed - indexed for MEDLINE]
8