Artemisia, Wormwood (Artemisia annua)

Artemisia annua is a medicinal plant that originated in Southeast Asia but is now cultivated all around the world. It has been used in traditional Chinese medicine for more than 2000 years as a treatment for fevers, inflammation, headaches, bleeding, and malaria, but its medicinal properties were rediscovered by modern science in the 1970’s when research revealed that the plant contains more than 10 active substances. Currently, Artemisia annua is the source for the production of artemisinin and semi-synthetic artemisinin derivatives (including dihydroartemisinin, artesunate, artemether, and arteether) that are used for the production of combination therapies for the treatment of malaria Today, one of those substances – artemisinin – is the foundation of all anti-malarial medicine, the discovery of which won Prof. Tu Youyou the Nobel Prize in 2015.

A. annua, may be effective for protozoal infections including leishmaniasis, Chagas’ disease, and African sleeping sickness. Cytotoxic effects of A. annua compounds have also been evaluated in tumor cell lines.

Artemisinin-based combination therapies are part of the standard treatment arsenal for malaria. Systematic reviews suggest it is as effective as quinine, but an increased risk of relapse may limit its uses. It is also unclear whether it is effective against quinine-resistant malaria strains. Other reports of artemisinin-based therapy resistance are also emerging, prompting additional drug development.

Artemisia, Wormwood (Artemisia annua)

Uses

The plants contained numerous chemical constituents including 3′,4′-dihydroxybonanzin, apigenin, betulinic acid, bonanzin, dehydroleucodine, dihydroluteolin, dracunculin and bis-dracunculin, helenalin, nepetin, scoparol, scopoletin, stigmasterol, (Z)-p-hydroxy cinnamic acid, β-sitosterol and others. In addition to artemisinin from A. annua, artemether and artesunate, further novel artemisinin derivatives and nanotechnological preparations may also be useful to combat Trypanosoma infections.

Chemistry/Pharmacology

Animal studies have suggested that artemisinin and related compounds inhibit tumor growth and metastasis. A few safety studies in advanced cancer patients suggest oral add-on artesunate, a semisynthetic artemisinin derivative, is well tolerated, although monitoring for ototoxicity is needed. In other studies, oral or intravenous artesunate did not produce a response, although modest clinical activity was observed with intravenous administration. In one study a low dose artemisia formulation produced clinically relevant pain reductions in patients with hip or knee osteoarthritis.

Clinical Studies

Artemisinin, the active constituent of A. annua, exerts antimalarial effects by free radicals formed via cleavage of the endoperoxide bond in its structure, which are responsible for eradicating the Plasmodium species.

Artemisinin induces apoptosis and cell cycle arrest of Leishmani donovani promastigotes, an intercellular parasite. It has antiproliferative effects on medullary thyroid carcinoma cells and induces apoptosis in a lung cancer cell line by modulating p38 and calcium signaling. In another study, it significantly inhibited cell growth and proliferation and caused G1 cell-cycle arrest in neuroblastoma cell lines. Dihydroartemisinin, a semi-synthetic derivative of artemisinin, demonstrates anti-inflammatory activity by attenuating COX-2 production via downregulation of serine/threonine kinase and MAPK pathways. Recent findings suggest that dihydroartemisinin-triggered apoptosis in colorectal cells occurs through the ROS-mediated mitochondria-dependent pathway.

Biomechanical Mechanism

Sources/Articles

Blanke CH, Naisabha GB, Balema MB, et al. Herba Artemisiae annuae tea preparation compared to sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria in adults: a randomized double-blind clinical trial. Trop Doct. Apr 2008;38(2):113-116.

Conlon CC, Stein A, Colombo RE, et al. Post-artemisinin delayed hemolysis after oral therapy for P. falciparum infection. IDCases. 2020;20:e00741.

Deeken JF, Wang H, Hartley M, et al. A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol. Mar 2018;81(3):587-596.

Ho WE, Peh HY, Chan TK, Wong WS. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther. 2014 Apr;142(1):126-39.

Hunt S, Stebbings S, McNamara D. An open-label six-month extension study to investigate the safety and efficacy of an extract of Artemisia annua for managing pain, stiffness and functional limitation associated with osteoarthritis of the hip and knee. N Z Med J. Oct 28 2016;129(1444):97-102.

Kim HG, Yang JH, Han EH, et al. Inhibitory effect of dihydroartemisinin against phorbol ester-induced cyclooxygenase-2 expression in macrophages. Food Chem Toxicol. 2013 Jun;56:93-9

Konig M, von Hagens C, Hoth S, et al. Erratum to: Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study. Cancer Chemother Pharmacol. Jun 2016;77(6):1321.

Konig M, von Hagens C, Hoth S, et al. Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study. Cancer Chemother Pharmacol. Feb 2016;77(2):413-427.

Lai H, Nakase I, Lacoste E, Singh NP, Sasaki T. Artemisinin-transferrin conjugate retards growth of breast tumors in the rat. Anticancer Res. 2009 Oct;29(10):3807-10.

Lu M, Sun L, Zhou J, Yang J.Dihydroartemisinin induces apoptosis in colorectal cancer cells through the mitochondria-dependent pathway. Tumour Biol. 2014 Jun;35(6):5307-14

McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria. Cochrane.Database.Syst.Rev. 2000;CD000527.

McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria. Cochrane.Database.Syst.Rev. 2000;CD000256.

Michaelsen, Friedrich-Wilhelm, Mohamed EM Saeed, Jörg Schwarzkopf, and Thomas Efferth. "Activity of Artemisia annua and artemisinin derivatives, in prostate carcinoma." Phytomedicine 22, no. 14 (2015): 1223-1231.

https://lavierebelle.org/IMG/pdf/2015_activity_of_artemisia_annua_and_artemisinin_derivatives_in_prostate_carcinoma-2.pdf
Mishina YV, Krishna S, Haynes RK, Meade JC. Artemisinins inhibit Trypanosoma cruzi and Trypanosoma brucei rhodesiense in vitro growth. Antimicrob Agents Chemother. May 2007;51(5):1852-1854.

Mu D, Zhang W, Chu D, et al. The role of calcium, P38 MAPK in dihydroartemisinin-induced apoptosis of lung cancer PC-14 cells. Cancer Chemother Pharmacol. Apr 2008;61(4):639-645.

Mueller MS, et al. Randomized controlled trial of a traditional preparation of Artemisia annua L. (Annual Wormwood) in the treatment of malaria. Trans R Soc Trop Med Hyg. 2004;98:318-21.

Payne AG. Exploiting intracellular iron and iron-rich compounds to effect tumor cell lysis. Med Hypotheses 2003;61:206-9.

Rath K, et al. Pharmacokinetic study of artemisinin after oral intake of a traditional preparation of Artemisia annua L. (annual wormwood). Am J Trop Med Hyg. 2004;70:128-32.

Rinner B, et al. Activity of novel plant extracts against medullary thyroid carcinoma cells. Anticancer Res 2004;24:495-500.

Ruperti-Repilado FJ, Haefliger S, Rehm S, et al. Danger of Herbal Tea: A Case of Acute Cholestatic Hepatitis Due to Artemisia annua Tea. Front Med (Lausanne). 2019;6:221.

Sen R, Bandyopadhyay S, Dutta A, et al. Artemisinin triggers induction of cell-cycle arrest and apoptosis in Leishmania donovani promastigotes. J Med Microbiol. Sep 2007;56(Pt 9):1213-1218.

Singh NP, Lai HC. Artemisinin induces apoptosis in human cancer cells. Anticancer Res. 2004 Jul-Aug;24(4):2277-80.

Skyles AJ, Sweet BV. Alternative therapies. Wormwood. Am J Health Syst.Pharm. 2004;61:239-42.

Stebbings S, Beattie E, McNamara D, et al. A pilot randomized, placebo-controlled clinical trial to investigate the efficacy and safety of an extract of Artemisia annua administered over 12 weeks, for managing pain, stiffness, and functional limitation associated with osteoarthritis of the hip and knee. Clin Rheumatol. Jul 2016;35(7):1829-1836.

van der Kooy F, Sullivan SE. The complexity of medicinal plants: the traditional Artemisia annua formulation, current status and future perspectives.J Ethnopharmacol. 2013 Oct 28;150(1):1-13.

van der Pluijm RW, Tripura R, Hoglund RM, et al. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial. Lancet. Apr 25 2020;395(10233):1345-1360.

von Hagens C, Walter-Sack I, Goeckenjan M, et al. Long-term add-on therapy (compassionate use) with oral artesunate in patients with metastatic breast cancer after participating in a phase I study (ARTIC M33/2). Phytomedicine. Feb 15 2019;54:140-148.

Willoughby JA Sr, Sundar SN, Cheung M, et al. Artemisinin blocks prostate cancer growth and cell cycle progression by disrupting Sp1 interactions with the cyclin-dependent kinase-4 (CDK4) promoter and inhibiting CDK4 gene expression. J Biol Chem. 2009 Jan 23;284(4):2203-13.

Xing J, Kirby BJ, Whittington D, et al. Evaluation of P450 inhibition and induction by artemisinin antimalarials in human liver microsomes and primary human hepatocytes. Drug Metab Dispos. 2012 Sep;40(9):1757-64.

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 Sep;17(11):856-61

Zheng GQ. Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med. 1994 Feb;60(1):54-7.

Zhu S, Liu W, Ke X, et al. Artemisinin reduces cell proliferation and induces apoptosis in neuroblastoma. Oncol Rep. 2014 Sep;32(3):1094-100.