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Artemisinin: From Malaria to Cancer lbeatment

by RobertJay Rowen,MD
fr ditor -in- Chief , I econd Op in in n

Artemisinin, the key ingredient treated with artemisinin again or with activity of artesunate, a derivative of
obtained from Artemisia annuc, has a long another drug.7 artemisinin. The effectiveness of
history of use as an antimalarial remedy. About twelve years ago, Dr. Leo artemisinin is reduced by catalase,
Artemisia annuo, or "sweet wormwood," is Galland and Dr. Herman Bueno worked dithiothreitol and alpha
mentioned in the Seclpes For 52 Kinds Of together in New York City and began Furthermore, Levander, et al. found
Diseases found in the Mawangdui Han using artemisinin as a broad spectrum that manipulation of the host antioxidant
Dynasty tomb, dating from 168 BC In that antiparasitic agent. defense status could provide prophylactic
work, the herb is recommended for use for "Artemisinin is a powerful oridant. I or therapeutic enhancement for the control
hemorrhoids. It is also mentioned in the haue used it orally to treat small bowel of malaria, In this study, mice were fed with
Zhou Hou Bei Ji Fang (Handbook of bacterial ouergrowth, Clostridial diets deficient in vitamin E or a diet
Prescriptions for Emergency Tfeatments) ouergrowth and (along with other herbal supplemented with cod liver oil, which
written in 840 A. D. The major active extracts, such as berberine, grapefruit seed would deplete antioxidants. Vitamin E
principal was first isolated in 1972, and extract and oregano oil) as a treatment for deficiency enhanced the antimalarial
investigators at the Walter Reed Army intestinal parasites." I"eo Galland, MD. action of artemisinin againstP yoelii,but
Institute of Research located and Very recently, news reports have selenium deficiency did not. A diet
crystallized the active component in 1984.r trumpeted Artemisinin as a leading containing 5% cod,liver oil had a very
Artemisinin and two synthetic treatment for malaria. Affected natione strong antimalarial action. tr
derivatives, artemether and sodium are calling for it to be accepted as the Artemisinin has been shown to work
artesunate, were evaluated in the 1970's. number one first line treatment, but the through oxygen and carbon based free
A number of the tropical countries have USA has blocked its acceptance as the radical mechanisms. Its etructure includes
conducted trials. In China in 1979, primary treatment, alleging yet more an endoperoxide bridge. Peroxides generate
wherein 2,099 patients infected with P studies are needed. free radicals in a Fenton type reaction when
uiua artd P falciparum. Artemisinin had For the past ten years, the Hoang exposed to unbound ferrous iron. Malaria,
good therapeutic effects and improved or medical family, with three generations of which grows in the erythroc5rtes, has the
cured all patients. Furthermore, the sophisticated physicians, have used opportunity to accumulate much excess
treatment with Artemisinin was without artemiginin in combination with several iron which can spill into the unbound form.
any obvious side effects. Artemisinin is also other herbe to treat cancer, and eliminate Electron microscopy hae confirmed
effective in cerebral malaria. Body necrosis material from the body; for destruction of plasmodium membranes
temperature of patients normalized within example, from wounds; from intestines of with morphology typical of free radical
72 hours, and asexual parasites were people who have ulcerative colitis, and mechanisms.
eliminated within 72 hours, However, from Crohn's disease. The efficacy of the With the knowledge of a high
there was a relapse ratn of 2wo.2 artemisinin compound is very impressive accumulation of iron in cancer cells,
In clinical trials in Vietnam, children for the treatment of breaet cancer and researchers Henry Lai and Narenda Singh
ages 1 to 15 years were randomly selected possibly to prevent it. It is not only of the University of Washington became
to receive artemisinin suppositories or oral because ofdirect anticancer activity, but interested in possible Artemisinin activity
quinine. The results indicated that the also due to hormonal balancing properties against malignant cells. In 1995, they
suppositories rapidly cleared aeexual P of the artemisinin. Herein. doses of 300 published a paper in Cancer Letters
Falciparium parasitemia in children and mg twice per day were adequate with concerning the use of artemisinin against
confirured the problem reoccurrence rates.s other herbs.s numerous cancer cell lines in uitro, This
Artemisinin has been extensively "The herb itself, Artemisia annua, is article has mobilized interest in
researched for malaria, and has been used one of thc best things for PMS, crarnping, artemisinin as an addition to anticancer
on over a million patients, mostly in China excessiue bleeding and all symptoms of treatment.rg
and Vietnam. It is very helpful for drug hyper-estrogenemia and hyper- There are a number of properties
resistant malaria. Extensive review prolactinemia." Dr. Hoang, MD. shared by cancer cells, which favor the
articles are available documenting the Artemisinin contains an internal selective toxicity of artemisinin against
extensive testing that has been done,aa peroxide group. Due to this group, reactive cancer cell lines, and against carrcer in uivo.
Various oral dosage regimens have oxygen is alreadypreeent in the molecule. In addition to higher rates ofiron flux via
been adopted in treating over one million This belief is in agreement with the transferren receptors than normal cells,
patients. Early studies suggested that an observations that derivatives of cancers are particularly sensitive to oxygen
optimum total dosage of 3 grams (about artemisinin lacking the peroxide moiety,
60 mglkg) was admirristered over a 3 to 5 are devoid of antimalaria activity.o A subsequent article appeared in Life
day period. In most cases parasite and Additional support for oxygen- Sci.encein 2001 by Singh and Lai on the
fever clearance times wer in less than two mediated toxicity of artemisinin is selective toxicity of artemisinin and
days. Recurrence were much more generated from other studies. The holotransferrin towards human breaet
common with tablets than with parenteral antimalarial activity of artemieinin in cancer cells.ra In this article, rapid and
formulations. Because of the very rapid uitro, agalnst P. falciparum, could be complete destruction of a radiation-
clearance time offever and parasites, the enhanced by increased oxygen tension. resiBtant breaet cancer cell line was
use of artemisinin was favored. and Drugs such as miconazole and achieved when the in uitro cell system was
recurrenceg, which were common. were doxorubicin, which are known to work via supported in iron uptake with
oxygen radical effects, enhance the holotransferrin. fire cancer cell line was


completely nonviable within 8 hours of The higher iron fluxes, especially
combinedincubation with minimal effect associated with the reproductive phase of Artemisinin
on the normal cells. tumor cells, should render these cells even
Artemisinin becomescytotoxic in the more susceptible to oxidative damage via used together. In combined treatment,
presenceofferrous iron. Since iron influx hydrogen peroxide and superoxides. considerable tumor cell death was
is naturally high in cancer cells, Normally, the profound catalaee deficiency observed at a concentration. of
artemisinin and ite analogeselectively kill in cancer cells is credited with creating dihydroartemisinin of 1 uM aft,er 8 hours
cancer cells under conditions in uiuo. vulnrerability to oxidants, in relationship of incubation. Furthermore, there is reason
Further, it is possible to increase or to W vitamin C or fV hydrogen peroxide. to believe that artemisinin can work at
enhanceiron flux in cancercells ueing the However, since all of these protective lower concentrations in uivo tltan in uitro,
conditions that increaseintracellular iron antioxidant enzymes are most often due to destruction of the artemisinin
concentrations. However, intact in uiuo deficient in transfonned cells. the oxidant molecule in uitro.
Bystemsdo not need holotransferrin, the vulnerability should be enhanced Lai suggests that this procedure would
Uving body provides all the necessaryiron dramatically, and further so, due to be most effective for the treatment of
transport proteins. enhanced unbound iron during cell aggressive cancers, in which large
A third paper, by Efferth et al., division. numbers of traneferrin receptors are
publishedinOncology in 2001stated that Dr. Hugh Riordan has suggested that expressed on the cell surface. It may not
the antimalarial artesunateis also active very high doses of fV vitamin C can kill be effective for T cell leukemias, which
against cancer.r6This article described cancer cells via conversion ofvitamin C to have defective internalization of
dramatic cytotoxicactivity againeta wide hydrogen peroxide, and due to defrciency transferrin receptors, and therefore may
variety of cancersincluding drug resistant of catalase. For this procedure to work, not be susceptible to this treatment.l2
cell lines. Artesunate (ART) is a semi- very high levels of IV vitamin C are
synthetic derivative of artemisinin, and required to reach "kill concen-trations." fV Caee reporte
has been analyzed for its anticancer vitamin C may be one of the best-
1. Patient D.A. a 47 year-old mechanic
activity against 55 cell lines by the documented alternative cancer who presented with a 4.5 cm. Non-
DevelopmentalTherapeutics program of treatmente.u
Hodgkin's lymphoma on the right side of
the National CancerInstitute, USA. ART Artemisinin may be a most elfective hie head, with gaping incision from a
was most active against leukemia and method, and certainly one ofthe easiest, recent biopsy, and tremendous
colon cancer cell lines. Mean growth ofdelivering a knockout oxidative stress inflammatory erythema. Artesunate,
inhibition 50% (GI 50) l.LlmicroM and to cancer cells. 60mgwas administered IM 14 consecutive
2.13 microM respectively.Non-small cell Artemisinin is appealing for oral uee days and he switched diets to high protein/
lung cancercell Iines showedthe highest in that the pharmacodynamics, dosage and vegetable (Kelley parasympathetic type
mean (GI50 26.62micmM) indicating the toxicity have been well studied for use in diet). At the end of two weeks, a depression
lowest sensitivity towards ART. relationship to the treatment of malaria.
appeared at the apex of the tumor. Four
Intermediate GI 50 values were obtained Artemieinin is relatively safe with little
weeks later, the mass was completely gone,
for melanomas,breast, ovarian, prostate, side effects even at high doeages (70 mgl skull surface smooth, incision totally
CNS, and renal cancer cell lines. Most kg per day) in short term malaria use. healed and erythema virtually cleared.
important, a comparison of ART's Artemisinin has two semisynthetic Apparantly cancer-free as of thie writing
cytotoxicity with thoeestandard cytostatic derivatives. Artegunate is a water-soluble
6 months later.
drugs showed that ART was active in derivative with no reported toxicity at 2. Patient V.M. an 83 year old Tbronto
molar ranges comparable to those of usual levels. However, its serum half-life
resident. Healthy most of her life, she now
egtablished antitumor drugs. Leukemia is relatively short. Artemether is a lipid
had a non-small cell lung carcinoma in the
lines resigtant to either doxorubicin, soluble derivative, effective in cerebral right lower lobe, considered non-resectable
vincristine, nethotrexate, or hydroxy-urea malaria, and therefore may be more because of heart failure and circulatory
were tested. Remarkably, none of these effective in brain cancers by better problems. She receivedArtemisinin 500mg
drug resistant lines showedresistanceto penetration of the blood-brain barrier.
BID from Allergy Research Group and
ART. lhe theorized reanon for this ie the Artenether, however, has been reported to
Carnivora oral, via nebulizer, 5cc BID. In
absenceof a tertiary amine inARl present cause some neural toxicity in laboratory 4 months the tumor shmnk to Lx2 cm and
in virtually all o*rer chemotherapyagents, models in rather high doees. Artemisinin
her oncologist felt this represented scar
which is required for cellular transport has an intermediate halflife and can cross
tissue and declared her cancer free. (Her
systemsto usher the drug outside the cell. the blood-brain barrier. The two heart condition improved considerably
semisynthetic derivatives are available with CoQ10, 600mg daily).
Crncer CelleAre Deficient in overseas in both oral and injectable for 3. Patient D.E., a 47 yeanold Alaska
Antioxidant Enz5rmes arteguante and artemether. resident with stage 4 breast cancer and
Cancer cells are notoriously deficient As mentioned. Lai ueed holo- metastases to T1 with significant pain,
in antioxidant enz5rmes- both forms of transferrin, which is iron-loaded vertebral collapse and local neurological
euperoxidedismutase, the manganese transferrin, to further sensitize tumor cell impairment. First seen May 2001, she
form in mitochondria, and the copper zinc lines to the oxidizing properties of received a series of IPT (insulin
form in the cell cytoplasm are generally dihydroartemisinin, which is derived from potentiation therapy-low dose
low in cancercells. Cancercells are grosaly the parent compound metabolically in uiuo, chemotherapy), high doee vitamin C
deficient in catalase and glutathione A human leukemia cell culture, Molt-4- infusiona, supplements, and dendritic cell
peroxidase, both of which degrade lymphblastoid cells, and normal human vaccine, dietary management (Kelly
hydrogen peroxide. It ie these deficiencies lymphocytes were used in this experiment. sympathetic type diet), and detoxification
in antioxidant enzymeswhich lead to the A significant decrease in cell count wasl strategies. Most symptoms had cleared
use of many of the common noted with artemisinin alone, with p<.035. within 4 months (Oetober 2001). In
chemotherapeutics which are superoxide Greater effects were noted when January 2002, she received artesunah fV
generators.16 transferrin and dihydroartemeisin were


other than feeling some nausea from the detoxification, diet, immune support,
Artemisinin abundance of nutritional supplements and spiritual work, etc. This use of
enzJrmes, through which ehe persevered' complementary strategies and
As of this submission, all treatmente are professional supervision cannot be
(source: mainland China), plus oral being tapered. emphasizedenough, especially since long
artemieinin 300 mg BID (ARG and Comment: This is a rather dramatic term use of artemisinin and/or its
Wellcare Pharma) which has been reversal ofan end stage cancer. I believe derivatives has had little study' The Hoang
continued.Six months later ehewas happy it shows the value of a comprehengive family has indicated to me a 5o-604olong-
to report shehas no symptomswhatsoever management strateg:y. Cancer ought to be ter:mremission in over 400 caneerpatients
and ia living a normal life. Her local macromanaged with multiple approaches utilizing artemisinin together with a
provider believes the regressedmass is instead of conventional approaches of comprehensivecancer strategy, and with
now scar tissue. single strategy management. While it is no observedtoxicity.
4. Patient F.A., an 81 Year-old too early to determine this caee's final I gratefully acknowledgeDrs. Lai and
Californian with multiple skin cancers outcome, clearly management was far lese Singh in their pioneering work and their
including one active recurrent quarter- expensive, far less toxic, and far more personal assistancein providing me with
sizedlesion that had beenburned 4 times effective than what might have been the information needed to work with
previously. Topical artemisinin (one expected from any conventional approach. artemisinin and its derivatives for the
capsuleARG artemisinin in 507oDMSO) The quality of her life has been far benefit ofmy patients.
appliedtwice daily causedthe large lesion superior, no mattr the final outcome.
to fall offwithin 5 days and other smaller All patients who took oral artemisinin Correspondence:
skin cancert to regress.His wife reported did so in the morning and evening on an Robert Jay Rowen, MD
the samewith her skin cancerg. empty stomach with either conjugated 95 MontgomeryDr., Suite 220
5. L.L.,is a WestCoastwomanin her linoleic acid and./or omega 3 supplements Santa Rosa,Califomia 95472USA
40's with breast cancer and extremely and/or some full fat cultured organic dairy Email:
painful metastesesall over her spine.She product to enhance absorPtion.
had receivedlimited radiation therapy to Simultaneous iron in the stomach might
reducethe pain in the thoracicspine prior neutralize its effectiveness. Beferences
to consulting me. She beganartemisinin, 1. Klayman D. Qinghaosu (Artemisinin):
Antimalarial Drugfrom China, Science,1985,Vol-
and a variety of complementarystrategies, Conclusion 238, May 31, p.1049
including diet, detoxifrcation and Kelly Artemisinin has been used for about 2. China CooperativeResarchGmup on Qinghaoeu
type proteolytic enzymes (from Allergy 30 years in Vietnam and China for cancer and its Derivativee as Antimalariale. J. Tfad.
Chin. Med.2, l7 ,1982.
ResearchGroup). Immediately, her energ'y treatment. And the experience with
3, KeithArnold, TtanTinh Hien, NSuyenlYan Chin,
exploded.Her pain level took a dive when artemisinin for this purpose io increasing. et al. A randomized comparative study of
she received treatment from an Edgar This history probably led to the recent artemieinine suppositoriesand oral quinine in
Cayce Foundation healer. Her comment cited cancer research with artemisinin. acute falciparum Malaria-
4, Tlarnactions of the Royal Society of Ttopical
after two weekgon artemisinin wae "Last The fact that artemisinin's direct
Medirinc and Hygiene (1990) 84:499'602.
week I thought I was dying and today for antineoplastic effects closely resemble tlnt 5. Bharel S, Gulati M, AMin P, Srivaetava S.
the first time in months, I believe I am of high-dose intravenous vitamin C is Structure biosynthesie and functions of
going to live." Four months into therapy intriguing. The potential benefit of artehisinin. FirobrapiaYoll')f,YII No 6, 1996'
6. Gulati A, Bharel S, Srivaatava M, Abdin MZ.
using oral supplementsalone (no IV artemisinin in cancer treatment should be Experimental Studieo on Artemisia, an herbal
therapy), d:ietand detoxification strategies, further explored because it is simple, safe, remedyfor malaria. FiaterapiaYol LXVll No 5,
a PET scan. the moet efficient and well-understood, and capitalizes on the r996.
7. HienT, WhiteN.Thc I'ancet 1993Vol841March
sensitive study for spreadofcancer,did not multifold weakness in cancer cells to
6 p 603-661.
show any activity anywhere in her spine, defend themselves against oxygen 8. Pereonalcommunicationfrom Dr, Hoang, M.D ,
evenin placesthatwere present beforeand radicals. Enhancing the oxidant activity 2002.
not radiated! Further. the scan did not with other oxidation agents (such as 9. Amee JR, Ryan MD, Klayman DL. Charge
tranrfer and ory radicsls in antimalarial action.
confirm defrnite cancer activity anywhere carnivora, ultraviolet blood irradiation,
J. FreeRad Biol. Med 1985,1:353-61.
else! H2O2, or higher or<ygentension itsel0 may 10. Krungkrai SR, YuthavonS. The antimalarial
5. Patient J.M., a 60 year-old womar add significant synergism. Adding action of Plasmodium falciparum of qinghaosu
with ovarian cancerpresentedto the office artemisinin to low dose chemo-therapeutic and artosunqte itrcombinstion with agents which
modulate oridant etress. Ihcn . l? Soc' Tltp. Med
wittr liver metastases,trans-aminases400- regimens inducing cytotoxicity via free Hyg 1987,8l:71&4.
600, WBC of 2600 and CA 125 of nearly radical mechanisms (such as doxorubicin), 11. Icvander OA, Ager AL, Morria VC. Qinghaoeu,
50. She had failed a complete cycle of full may safely add to the effectiveness ofsuch dietary vitamin E, selenium aod cod liver oil:
affect on auaceptibility of mice to the malarial
dose chemotherapy a few years ago. Her treatment,
pararite Plarmodium yoelii. Arn, J. Clin. Nutr'
appe0itewas still intact, but reduced. She Ih. Singh, in a pertbnal communication 1989;6:34&62.
receiveddetoxification, I&lly sympathetic to me, has ghared that he has been 12. l,ai H., Nareodra S. Cancer [4tters,9lt4l'48,
diet, pancreatic enzymes, low dose following a series of cancer patients with 1996.
13. May WS. JMembr. Biol., 88:206-216,1986.
chemotherapy (via insulin potentiation nearly universal improvement on
14, Singh NP, Lai H. Zife Sci Nov 21' 70(1):49-56,
therapy), artemieinin 400mg BID (Allergy artemisinin or its derivatives, He believes 2001.
Reeearch Group), oral Carnivora artemisinin will prove to be the moet 15. Efrerth T, Dunstan H, SsuerbreyA, Miyachi H,
( high dose powerful, yet extremely inexpensive and Chitambar CR. Antimalarial arteeunate ie also
ac{ive against carce4 Oncol. 2001, Apr:,L8/,4):7
intravenous vitamin C. By the eighth safe, chemotherapeutic agent yet found, 73.
week, all enzJrmeswere 20-30 except the and efective orally for home use. However, 16. Irvire SA, Kidd PM. AntioridantMaPtation: Its
GGT which had fallen to 110,WBC was like myself, he and the Hoang family of Role in Free Radicsl Pathology.Allergr Research
physicians, believes it should only be used Group, San Leandro, CaMornia, 1985.
6000 and CA 125 was well within the 17. Journol of Orthomolecular Medicine, Spe;cial
normal range. There was no physical or in a professional atmosphere together with Edition,1999.
laboratory toxicity observedin the regimen complementary strategies employing a