LA UNIVERSIDAD AUTONOMA DE TLAXCALA PIONERA EN EL CULTIVO DE ARTEMISIA ANNUA

ARTEMISININA 1200 MAS EFECTIVA QUE LAS DROGAS PARA EL CANCER

CULTIVO AGROECOLOGICO DE ARTEMISIA ANNUA EN FARMACIA VERDE UNIVERSITARIA TLAXCALA MEXICO

PRODUCTOS A BASE DE ARTEMISIA ANNUA DE CULTIVO AGROECOLOGICO EN MEXICO

ARTEMISININA 1200 MAS EFECTIVA QUE LAS DROGAS SINTETICAS PARA EL CANCER

What is it?

Artemisia annua, also known as sweet wormwood, sweet annie, sweet sagewort and annual wormwood (Chinese: qīnghāo), is a common type of wormwood that is native to temperate Asia but naturalized throughout the world.1 It belongs to the family of Asteraceae and has fern-like leaves, bright yellow flowers and a camphor-like scent. Glandular structures (trichomes) producing a wide range of bioactive compounds (mostly terpenoids) can be found on the surface of leaves, stems and flowers.

Ingredient(s)

The phytochemical composition of A. annua has been reviewed in great detail by Bhakuni et al.2 The most relevant compounds are sesquiterpenoids (ex. artemisinin), triterpenoids, flavonoids (polymethoxylated flavonoids), chromenes1 and essential oil components. The content of an A. annua extract depends on the solvent used for extraction. Aqeous extracts seem to contain less polymethoxylated flavonoids than alcohol extracts, but they do contain a high amount of mono-caffeoyl- and mono-feruloyl-quinic acids, di-caffeoyl- and di-feruloyl-quinic acids. Alcoholic extracts seem to contain the highest antioxidant potential. Also the flavonoids casticin and artemetin that have shown synergism with artemisinin against malaria are less extracted in aqeous extracts.3-5
Besides A. annua itself, this summary also reviews current literature on artesunate, dihydroartemisinin and artemether, which are semi-synthetic derivatives of artemisinin. Far more research has been published on the effect of these compounds than on artemisinin itself. Arteether, another semisynthetic derivative that has been used in antimalarial treatment has not been the focus of anticancer research to date.

Application and dosage

There is no documented safe or effective dose for the possible use of A. annua derived products for the treatment of cancer in adults or children. The Chinese pharmacopoeia lists the dry herb as a remedy for fever and malaria. The daily dose described is 4.5 to 9 grams of dried herb to be prepared as a tea infusion with boiling water. The artemisinin content varies from 0.02% to 1.1% of the dry weight.6 In addition, artemisinin and its semisynthetic derivatives are used in antimalarial treatment in artemisinin-based combination therapies, with daily doses between 100 and 200mg.7

History

Artemisia annua was used by Chinese herbalists in ancient times to treat specific fevers, but had fallen out of common use until it was rediscovered in 1970 when the Chinese Handbook of Prescriptions for Emergency Treatments (340 AD) was recovered. This ancient pharmacopeia contained a recipe for a tea from the dried leaves of A. annua to be used in case of specific fevers. In 2010 it was discovered that A. annua has already been cited in the earliest Chinese medical prescriptions, the Mawagndui tomb texts dating back to 168 B.C. There, it is prescribed for female haemorrhoids and as a sexual tonic, being mixed with other herbs, including cinnamon and ginger, and administered in boiled urine.8 In 1971, scientists demonstrated that the plant extracts had antimalarial properties in primate models.9

Mechanism of anti-cancer action

Artemisinin, the natural endoperoxide of A. annua, and its semisynthetic derivates dihydroartemisinin, arthemether, artheether and artesunate are considered to be the primary active constituents for antimalarial and anti-cancer activity.10,11Also the polymethoxyflavonoids are indicated as important compounds with potential anticancer activity. Cancer cell lines show a differential sensitivity as well as resistance to this group of compounds. Different genes which influence the sensitivity or the resistance to treatment have been identified. These genes could potentially function as markers indicating the expected efficacy of a clinical therapy.12,13 In contrast to popular belief that the cytotoxic activities would only be due to the non-specific generation of reactive oxygen species, it has become clear that artemisinin-related endoperoxides additionally have various specific molecular targets and can significantly influence the expression of key regulatory proteins of the cell cycle.10,11,13,14 Artemisinin-related endoperoxides were found to significantly inhibit angiogenesis and also to induce apoptosis.10,15 Iron plays a crucial role in the cytotoxic activities of artemisinin-related endoperoxides through the generation of both ROS and carbon-centred radicals. In general, the addition of iron has been shown to enhance both the cytotoxicity and selectivity of the treatment, but not in all cell lines.10,15
AMDT is a sesquiterpene found in the hairy roots of A. annua. It has been demonstrated that it induces apoptosis through the mitochondrial dependent pathway in human lung 95-D cells. Cytotoxicity of this compound was also found in ovary, liver, and cervix cancer cells.16
No cross-resistance has been found between the artemisinin-related as well as the unrelated compounds, so cells resistant to one compound retain sensitivity to another one.17

Alleged indications

Apart from malaria, A. annua is also used in cases of fever, headaches, infections and inflammations.18 It has been claimed to kill cancer cells and to be especially effective in breast cancer and leukaemia.19,20

Prevalence

There are no data available on the prevalence of use of A. annua in the treatment of cancer.

Legal issues

There are no A. annua derived drugs that are approved for cancer treatment.

Cost(s) and expenditures

Prices available on the internet for artesunate range between US $0.30 and 0.70 for a 100mg tablet or capsule, i.e. the price for a one-month supply ranges from US$ 9 to 21 at a daily dose of 100mg.

« Abstract and key points

Does it work? »

Citation

Klara Rombauts, Arne Heyerick, CAM-Cancer Consortium. Artemisia annua [online document]. http://www.cam-cancer.org/CAM-Summaries/Herbal-products/Artemisia-annua. January 29, 2015.

Document history

Assessed as up to date in January 2015 by Barbara Wider.
Summary assessed as up to date in August 2013 by Barbara Wider.
Summary fully revised and updated in August 2012 by Klara Rombauts.
Summary first published in March 2011, authored by Klara Rombauts and Arne Heyerick.

References

1. Wikipedia, the free encyclopedia 2012. Available from: URL: http://en.wikipedia.org/wiki/Artemisia_annua, accessed 27 July 2012.
2. Bhakuni, R.S., Jain D.C., Sharma, Kumar. Secondary metabolites of Artemisia annua and their biological activity. Current Science, 2001 Jan 10;80(1):35-48.
3. Carbonara T, Pascale R, Argentieri MP, Papadia P, Fanizzi FP et al. Phytochemical analysis of a herbal tea of Artemisia annua L. J Pharm Biomed Anal 2012;62:79-86.
4. Iqbal S, Younas U, Chan KW, Zia-Ul-Haq M, Ismail M. Chemical composition of Artemisia annua L. leaves and antioxidant potential of extracts as a function of extraction solvents. Molecules 2012;17:6020-6032.
5. Weathers PJ, Towler MJ. The flavonoids casticin and artemetin are poorly extracted and are unstable in an Artemisia annua tea infusion. Planta Med 2012;78(10):1024-6.26. McGovern PE, Christofidou-Solomidou M, Wang W, Dukes F, Davidson T and El-Deiry WS. Anticancer activity of botanical compounds in ancient fermented beverages (review). Int J Oncol 2010;37:5-14.
6. Natural Standard. Monograph on Artemisia annua. Natural Standard 2010Available from: URL:www.naturalstandard.com, accessed 27 July 2012.
7. World Health Organization. WHO monograph on good agricultural and collection practices (GACP) for Artemisia annua L. 2006.
8. McGovern PE, Christofidou-Solomidou M, Wang W, Dukes F, Davidson T, El-Deiry WS. Anticancer activity of botanical compounds in ancient fermented beverages (review). Int J Oncol. 2010 Jul;37(1):5-14.
9. van Agtmael MA, Eggelte TA, van Boxtel CJ. Artemisinin drugs in the treatment of malaria: from medicinal herb to registered medication. Trends Pharmacol Sci 1999 May;20(5):199-205.
10. Firestone GL, Sundar SN. Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev Mol Med 2009;11:e32.
11. Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets 2006 Apr;7(4):407-21.
12. Li LN, Zhang HD, Yuan SJ, Yang DX, Wang L, Sun ZX. Differential sensitivity of colorectal cancer cell lines to artesunate is associated with expression of beta-catenin and E-cadherin. Eur J Pharmacol 2008 Jun 24;588(1):1-8.
13. Huang XJ, Ma ZQ, Zhang WP, Lu YB, Wei EQ. Dihydroartemisinin exerts cytotoxic effects and inhibits hypoxia inducible factor-1alpha activation in C6 glioma cells. J Pharm Pharmacol 2007 Jun;59(6):849-56.
14. Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer 2007 Sep 15;121(6):1360-5.
15. Chen HH, Zhou HJ, Wu GD, Lou XE. Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology 2004 May;71(1):1-9.
16. Zhai DD, Supaibulwatana K, Zhong JJ. Inhibition of tumor cell proliferation and induction of apoptosis in human lung carcinoma 95-D cells by a new sesquiterpene from hairy root cultures of Artemisia annua. Phytomedicine 2010;17:856-861.
17. Efferth T, Herrmann F, Tahrani A, Wink M. Cytotoxic activity of secondary metabolites derived from Artemisia annua L. towards cancer cells in comparison to its designated active constituent artemesinin. Phytomedicine 2011;18(11):959-969.
18. Memorial Sloan Kettering Cancer Center. MSKCC summary on Artemisia annua L. Memorial Sloan Kettering Cancer Center 2010Available from: URL: http://www.mskcc.org/mskcc/html/69126.cfm, accessed July 2012.
19. Singh NP and Lai H. Selective cytotoxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci 2001;70(1):49-56.
20. Singh NP and Lai H. Synergistic cytotoxicity of artemesinin and sodium butyrate on human cancer cells. Anticancer Res 2005;25:4325-4332.
21. Zhang ZY, Yu SQ, Miao LY, Huang XY, Zhang XP, Zhu YP, et al. [Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial]. Zhong Xi Yi Jie He Xue Bao 2008 Feb;6(2):134-8.
22. Singh N.P., Verma K.B. Case report of a laryngeal squamous cell carcinoma treated with artesunate. Archive of Oncology 2002;10(4):279-80.
23. Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, et al. Artesunate in the treatment of metastatic uveal melanoma--first experiences. Oncol Rep 2005 Dec;14(6):1599-603.
24. Singh NP, Panwar VK. Case report of a pituitary macroadenoma treated with artemether. Integr Cancer Ther 2006 Dec;5(4):391-4.
25. Campos S, de la Cerda P, Rivera A. Fatal artesunate toxicity in a child. Journal of Pediatric Infectious Diseases 2008;3(1):69-75.
26. Panossian LA, Garga NI, Pelletier D. Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol 2005 Nov;58(5):812-3.
27. Gordi T, Lepist EI. Artemisinin derivatives: toxic for laboratory animals, safe for humans? Toxicol Lett 2004 Mar 1;147(2):99-107.
28. Shen M, Ge HL, He YX, Song QL, Zhang HZ. Immunosuppressive action of Qinghaosu. Sci Sin B 1984 Apr;27(4):398-406.
29. Brinker F. Herb Contraindictions and Drug Interactions. Ecletic Medical Publications 2001
30. Skyles AJ, Sweet BV. Alternative therapies. Wormwood. Am J Health Syst Pharm 2004 Feb 1;61(3):239-42.

Legal notice
The present documentation has been compiled by the CAM-CANCER Project with all due care and expert knowledge. However, the CAM-CANCER Project provides no assurance, guarantee or promise with regard to the correctness, accuracy, up-to-date status or completeness of the information it contains. This information is designed for health professionals. Readers are strongly advised to discuss the information with their physician. Accordingly, the CAM-CANCER Project shall not be liable for damage or loss caused 

Artemisia Annua come cura anticancro: il punto di vista dell'Istituto

Milano, 13 febbraio 2015. Alcuni siti Internet stanno diffondendo la notizia che l'Artemisia Annua può essere utilizzata efficacemente nella cura contro il cancro. Stiamo parlando di una piccola pianta erbacea appartenente alla famiglia delle Asteraceae, originaria della provincia di Hunan in Cina. Com'è noto, la Rete contiene una grande mole di informazioni mediche, non sempre affidabili sia dal punto di vista della correttezza clinico-scientifica sia da quello dell'indipendenza delle fonti. Gli articoli online sull'Artemisia Annua hanno suscitato in molti pazienti oncologici nuove speranze di guarigione, tanto che alcuni di loro si sono rivolti ai medici dell'Istituto per avere informazioni aggiornate sulle proprietà terapeutiche di questa erba, frettolosamente e incautamente presentata come "magica". Facciamo un po' di chiarezza su questo argomento.

In merito all'utilizzo dell'Artemisia Annua come farmaco antitumorale, si può dire con certezza che, in esperimenti in vitro, uno dei suoi principi attivi, l'artemisinina e i suoi derivati, hanno dimostrato un effetto tossico sulle cellule tumorali e che questa classe di farmaci è utilizzata come trattamento della malaria con un profilo di tossicità estremamente favorevole. Alcuni ricercatori dell'Istituto Nazionale dei Tumori sono direttamente coinvolti nella valutazione di un altro principio attivo dell'Artemisia Annua, la diidroartemisinina, e del suo ruolo antineoplastico valutato per ora sempre su modelli preclinici: i risultati sono convincenti ed è in corso di preparazione una pubblicazione scientifica.

In merito all'uso clinico i dati disponibili in letteratura sono limitati a un solo studio cinese in pazienti affetti da tumore del polmone "non a piccole cellule" che ha confrontato l'utilizzo di chemioterapia (cisplatino e vinorelbina) in combinazione o meno con artesunato (un derivato semisintetico dell'artemisinina) e qualche "case report" con diversi preparati e vari dosaggi, in combinazione con differenti trattamenti chemioterapici in neoplasie con varia eziologia. Lo studio cinese, purtroppo, non ha dimostrato che l'aggiunta di artesunato modifichi la durata della sopravvivenza dei malati e i "case report" sono molto difficili da interpretare e hanno scarso valore per la generalizzazione di una cura. In pratica, a oggi non esistono studi clinici che possano darci informazioni di quello che l'Artemisia Annua e i suoi derivati producono nell'uomo, sia come tossicità sia come efficacia antineoplastica.

In sintesi, per informare correttamente i cittadini e i pazienti, al momento attuale possiamo dire che:

1. i modelli preclinici ci fanno considerare artemisinina una molecola promettente in patologie selezionate;
2. l'emivita di questi farmaci (ovvero la "sopravvivenza" del principio attivo all'interno dell'organismo) è molto breve, al punto che come farmaco antimalarico è necessario somministrarlo in combinazione a un altro trattamento perché sia effettivamente efficace;
3. la dose utile come farmaco antineoplastico nei modelli in vitro è molto superiore a quella utilizzata nei preparati antimalarici;
4. i diversi preparati di Artemisia Annua hanno diverse emivite e diversi profili di distribuzione e tossicità;
5. non sappiamo quale sia la vera percentuale del principio attivo presente nelle differenti formulazioni di Artemisia Annua disponibili online o nelle erboristerie;
6. non esistono studi clinici validi che dimostrino l'efficacia e la sicurezza di questi preparati nell'essere umano.

Detto in parole semplici, non conosciamo ancora che tipo di prodotto scegliere, quale dose abbia una risposta antitumorale nell'uomo e con quali effetti collaterali, dunque siamo ancora lontani dal poter affermare con certezza che l'artemisinina e i suoi derivati siano utilizzabili con sicurezza nell'uomo e veramente utili nel trattamento dei tumori.

Queste sono le ragioni per cui nessun medico oncologo e ricercatore può consigliare una dose, un preparato specifico e una schedula di somministrazione dell'Artemisia Annua che possa essere, su solide basi scientifiche, efficace e sicuro. Inoltre, le interazioni con alcuni farmaci biologici o chemioterapici non sono completamente note quindi si sconsiglia vivamente, ai pazienti che fossero in trattamento con terapie standard, l'assunzione di parafarmaci o prodotti erboristici a base di Artemisia Annua senza informare i medici curanti. Esistono invece molte opzioni di cura nell'ambito di sperimentazioni cliniche già in corso presso l'Istituto Nazionale dei Tumori con farmaci promettenti, ma anche in questi casi bisogna essere coscienti che il concetto di sperimentazione, se da una parte rappresenta una speranza, dall'altra implica un'incertezza e non una sicurezza.

La Direzione Scientifica

Per maggiori informazioni, è possibile contattare l'Ufficio Relazioni con il Pubblico:
Mail: urp@istitutotumori.mi.it