Malaria is a deadly disease. Because of its reliance on tropical mosquitos for transmission, it disproportionately affects people living in the developing world: of the more than 600,000 deaths from malaria every year, over 90% occur in sub-Saharan Africa where resources are few and transportation to care facilities is difficult.1 What’s more, over the last fifty years the malaria parasite has evolved considerable resistance to tried-and-true treatments (such as chloroquine, quinine and its derivatives, along with other drugs such as sulfadoxine) in most areas where the disease is widespread.2 That’s why most physicians in the developing world are now using a class of drugs derived from a molecule called artemisinin. This compound is very effective against the malaria parasite, and is derived from Artemisia annua (Sweet Annie, or quing hao as it is known in the Chinese materia medica).3 It forms the cornerstone of current antimalarial therapy in the developing world. Unfortunately, isolating artemisinin from the whole plant has led to the development of drug resistance – still localized mostly to Southeast Asia, and not very widespread.4 Nevertheless, as combination artemisinin therapies are our best treatment for malaria, even these first signs of resistance are a cause for concern!
Malaria parasites first enter the liver, where they incubate for one to four weeks and then flood the bloodstream. They then enter red blood cells, where they feed on hemoglobin and clone themselves until the red blood cell bursts, spreading more parasites to infect more red blood cells. The cycles of feeding and reproduction underlie the cycles of fever that malaria patients suffer. Artemisinin and its allied molecules are able to create a burst of oxidative “free radicals” when they enter the red blood cell and interact with the iron-containing porphyrin ring (known as “heme”) at the heart of the hemoglobin protein during the parasite’s hemoglobin digestion process.5 Other mechanisms are at work as well: artemisinin seems able to bind to important gene-regulation proteins that govern cellular division, thereby affecting the parasite’s ability to clone itself. These actions damage the parasites, prevent their reproduction, and dramatically help the immune system overcome the infection. But what’s interesting is that these same mechanisms can also be of use in cases of autoimmune disease,6 other infections,7 and – of particular interest – cancer.8
It seems that the compounds in A. annua act as both cytotoxic agents – similar, in some ways, to certain types of conventional chemotherapy – and also as agents that modify the expression of genes. In the former case, the cytotoxicity of artemisinin-like compounds seems to rely on an abundance of iron to achieve the same “free radical” oxidative burst effect seen in the treatment of malaria. This also helps explain why there is little toxicity to non-malignant cells: cancer cells internalize iron at a much greater rate than healthy cells do (perhaps through increased transferrin surface receptors9, and are therefore more vulnerable to the iron-linked cytotoxicity of artemisinin.10 But in the latter case, A. annua compounds have reduced the expression of genes involved in cellular division, in inflammation, and in the production of new blood vessels – all areas that are essential to tumor growth and survival. At the same time, these same compounds seem to increase the expression of genes related to apoptosis, or programmed cell death.
Dr. Thomas Efferth is the chair of the department of Pharmaceutical Biology at the University of Mainz, in Germany. His research over the years has taken him to many places, from the forests of Yunnan in China to his current academic role, but he has always maintained a focus on medicinal plants and their roles in cancer therapy. Familiar with concepts from Chinese medicine as well as modern biochemistry, he is able to bridge disparate areas of research, allowing him to explore unthought-of connections like the potential application of A. annua in cancer therapy. He summarizes the last two decades of research in his most recent review article, “From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy.”11 The research points to exciting potential for this herb in a range of cancers, from non-solid cancer cell lines like those that underlie leukemia, to breast, colon, ovarian, liver, and pancreatic cancers. Much of the activity seems related to compounds other than artemisinin (like, for example, the ubiquitous
flavonoids), though that all-important molecule does seem to make this particular plant stand out. But, as we’re finding more and more, might it be possible that whole-plant preparations, with their complex synergy of chemistry that can both improve bioavailability and also enhance anti-tumor and antimalarial activity,12 are the preferable way to go?
I certainly hope this is the case. One of the big concerns around combination artemisinin / artesunate therapies is the high cost of treatment and limited distribution of the medicines, especially to low-resource sub-Saharan settings.13 Another is that, as we’ve seen, resistance to artemisinin is a growing concern. It turns out that resistance to whole-plant A. annua preparations doesn’t really occur as easily (and can even help reverse resistance in certain cases.14 This most recent discovery is part of the tireless research on A. annua conducted by Pamela Weathers of Worcester Polytechnic, here in the Northeastern US. Her lab has focused on a range of topics, including how to maximize potency and yield when growing A. annua,15 how to harvest and prepare the whole herb for use as an antimalarial,16 and more. When I had the privilege of meeting her recently, she brought a potted Artemisia with her to a panel discussion on Lyme disease – honoring the plant first and foremost before any conversations on how to use it as medicine. This impressed me, and put Dr. Weathers firmly in the camp of researchers like Dr. Efferth and Dr. Kevin Spelman (who has advocated for whole-plant therapy in the treatment of malaria for a long time.17
In any event, whether supporting local efforts in East Africa to grow this amazing plant as a sustainable, accessible, low-cost alternative to conventional antimalarials that also helps slow an emergent resistance problem, or considering Artemisia annua as a useful adjunct in cancer therapy, I hope that we can remember that naturally-occurring pharmacological synergies found in whole-plant preparations are often (and certainly in this case) more effective than molecular isolates. It’s time to go back to basics and consider the therapeutic potential of a simple cup of tea: it may seem simple, but it is many ways a much richer, complex, powerful and sustainable intervention.
1. US Centers for Disease Control and Prevention, https://www.cdc.gov/malaria/malaria_worldwide/impact.html
2. World Health Organization. "Global report on antimalarial drug efficacy and drug resistance 2000-2010." Global report on antimalarial drug efficacy and drug resistance 2000-2010. (2010).
3. Hsu, Elisabeth. "Reflections on the ‘discovery’of the antimalarial qinghao." British journal of clinical pharmacology 61.6 (2006): 666-670.
4. World Health Organization. Update on Artemisinin Resistance – January 2014. Geneva: World Health Organization; 2014.
5. Meshnick, Steven R. "Artemisinin: mechanisms of action, resistance and toxicity." International journal for parasitology 32.13 (2002): 1655-1660.
6. Li, Wei-dong, et al. "Dihydroarteannuin ameliorates lupus symptom of BXSB mice by inhibiting production of TNF-alpha and blocking the signaling pathway NF-kappa B translocation." International immunopharmacology 6.8 (2006): 1243-1250.
7. Liu, Rong, et al. "Efficacy of praziquantel and artemisinin derivatives for the treatment and prevention of human schistosomiasis: a systematic review and meta-analysis." Parasites & vectors 4.1 (2011): 201.
Efferth, Thomas, et al. "The antiviral activities of artemisinin and artesunate." Clinical Infectious Diseases 47.6 (2008): 804-811.
8. MIYACHI, HAYATO, and CHRISTOPHER R. CHITAMBAR. "The anti-malarial artesunate is also active against cancer." International journal of oncology 18 (2001): 767-773.
9. Shterman, N., B. Kupfer, and Ch Moroz. "Comparison of transferrin receptors, iron content and isoferritin profile in normal and malignant human breast cell lines." Pathobiology 59.1 (1991): 19-25.
10. Kelter, Gerhard, et al. "Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate." PLoS One 2.8 (2007): e798.
11. Efferth, Thomas. "From ancient herb to versatile, modern drug: Artemisia annua and artemisinin for cancer therapy." Seminars in Cancer Biology. Academic Press, 2017.
12. Ferreira, Jorge FS, et al. "Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer." Molecules 15.5 (2010): 3135-3170.
13. Goodman, Catherine, Paul Coleman, and Anne Mills. "Economic analysis of malaria control in sub-Saharan Africa." Geneva: Global Forum for Health Research, 2000.
14. Elfawal MA, Towler MJ, Reich NG, Weathers PJ, Rich SM. 2015 Dried whole plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin. PNAS USA 112(3):821-6.
15. Arsenault PR, Vail D, Wobbe KK, Weathers PJ 2010 Effect of sugars on artemisinin production in Artemisia annua L.: transcription and metabolite measurements - 2011.
16. Elfawal, M.A., Towler, M.J., Reich N.G., Golenbock, D.T., Weathers, P.J., Rich, S.M. 2012 Dried whole plant Artemisia annua as an antimalarial therapy. PLoS ONE 7(12): e52746.
17. Spelman, Kevin. "“Silver Bullet” Drugs vs. Traditional Herbal Remedies: Perspectives on Malaria." Herbal Gram 84 (2009).
