Artemisinin is a potent and widely used anti-malarial drug. Based on evidence demonstrating its treatment success, many infectious disease experts believe that intravenous artesunate IV should be the treatment of choice for malaria. It is proven to be an effective anti-malarial treatment and better tolerated than quinidine-based treatments (1).

Over the past decade, additional therapeutic uses for artemisinin have emerged. Research has found artemisinin is selectively toxic to cancerous cells (causing cancer cell death or apoptosis), is anti-angiogenic (inhibiting the formation of tumor blood vessels), demonstrates anti-HPV activity and exhibits immune-modulating behavior.

ANTI-CANCER & ANTI-VIRAL PROPERTIES OF ARTEMISININ

In malaria parasites, artesunate achieves its toxic effects by interacting with iron inside the food vacuole of the parasites. In human cancer cells, Artesunate initiates programmed cell death from the ensuing molecular damage caused by reactive oxygen species (ROS) generated by a reaction with iron (2-3).

HPV & CERVICAL CANCER:

Studies have demonstrated Artemisinin to have growth-inhibiting effects with certain cancer cell lines, such as cervical cancer cells (4). Nearly all cervical cancers are etiologically attributable to human papillomavirus (HPV) infection and pharmaceutical treatments targeting HPV-infected cells would be of great medical benefit. Research has found the predominant cancer cytotoxic components of artemesinin to be DHA (dihydroartemisinin, an active metabolite of artemisinin) and artesunate (a derivative of artemisinin). In pre-clinical studies, DHA was found to be highly selective in its toxicity to cervical cancer cells, with no effect on normal cervical cells, making it a desirable anti-cancer agent. The same study found DHA is cytotoxic to all immortalized HPV-expressing cell lines and that the expression of HPV genes makes the particular cancer cell line more sensitive to DHA (5).

A clinical study on a lipophilic artemesinin derivative for advanced cervical cancer in African women demonstrated excellent tolerability and a reduction in symptoms and markers of cancer growth. Although it was a small study, all patients in the study achieved clinical remission (6). The apparent effect of symptom disappearance and prolonged survival observed in this study warrant larger randomized controlled trials using a prolonged and possibly continuous period of artemisinin administration.

HPV & HEAD/NECK CANCERS:

HPV is also known to cause cancers in other areas of the body, such as the oral cavity and nasopharynx. An animal study examined the effect of artesunate IV on epithelial HPV infected cells and found that DHA’s cytotoxic effect inhibited tumor growth (7).

CMV & PNEUMONIA:

Cytomegalovirus (CMV) can present as an acute or chronic infection affecting a particular type of white blood cell known as monocytes. Studies support artesunate’s efficacy as a CMV treatment agent and demonstrate its ability to reduce lung fibrosis in CMV-pneumonia (8).

HEPATITIS C VIRUS & LIVER CANCER:

Artesunate demonstrated anti-viral activity against the Hepatitis C Virus (HCV). According to a recent cell study, the combination of interferon therapy (INF) and artesunate was a more potent inhibitor of viral replication than INF alone (9). HCV is known to be a causative factor in the development of hepatocellular (liver) cancer. Treatment with artesunate may have a role in preventing and treating hepatocellular malignancies.

ACUTE MYELOID LEUKEMIA:

In cell culture and animal studies, intermittent cycles of artesunate inhibited the growth of several different types of human acute myeloid leukemia (AML). Further, the combining of artesunate IV with established anti-leukemic drugs and newer tyrosine kinase inhibitors demonstrated better growth inhibition than either treatment alone (10).

LOCALLY ADVANCED BREAST CANCER:

A recent phase I clinical study in patients with locally advanced breast cancer proved that an IV artesunate is safe in doses of up to 200mg/day as an add-on therapy to ongoing oncological treatment (11).

COLORECTAL CANCER:

A small, randomized double-blind placebo-controlled trial involving 20 patients with colorectal cancer found pre-surgical treatment with artesunate IV dramatically reduced the risk of cancer recurrence (12). At a mean follow-up of 42 months, only 1 patient in the artesunate group had a recurrence compared to 6 in the placebo group. The trial certainly provides a strong directive for further clinical investigation. The Artesunate IV is among the most promising anti-metastatic agents in the post-surgical setting for colorectal cancer. Other agents with post-surgical anti-metastatic benefit include aspirin, ketorolac, celebrex, and cimeditine (13-16).

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References:

1. Hess KM, et al. Intravenous artesunate for the treatment of severe malaria. Ann Pharmacother. 2010 Jul-Aug;44(7-8):1250-8.

2. O’Neill PM, Posner GH. A medicinal chemistry perspective on artemisinin and related endoperoxides. J Med Chem 2004;47:2945–64.

3. Posner GH, O’Neill PM. Knowledge of the proposed chemical mechanism of action and cytochrome P450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides. Acc Chem Res 2004;37:397–404.

4. Chen HH, Zhou HJ, Fang X. Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. Pharm Res 2003;48:231–6.

5. Disbrow, G, Baege A, Kierpiec A, et al. Dihydroartemisinin is Cytotoxic to Papillomavirus-expressing Epithelial Cells In vitro and In vivo. Cancer Res 2005;65:23

6. Jensen FH, et al. First study of oral Artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markers. Anticancer Res. 2011 Dec;31(12):4417-22.

7. Disbrow GL, et al. Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo. Cancer Res. 2005 Dec 1;65(23):10854-61.

8. Zeng AH, et al. Human embryonic lung fibroblasts treated with artesunate exhibit reduced rates of proliferation and human cytomegalovirus infection in vitro. J Thorac Dis. 2015 Jul;7(7):1151-7.

9. Dia R, et al. Artesunate, an anti-malarial drug, has a potential to inhibit HCV replication. Virus Genes. 2016 Jan 6. [Epub ahead of print]

10. Fox JM, et al. Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs. Oncotarget. 2016 Jan 12.

11. Konig M, 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. 2016 Jan 21. [Epub ahead of print]

12. Krishna S, et al. A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer. EBioMedicine. 2015 January; 2(1): 82–90.

13. Restivo A, et al. Aspirin as a neoadjuvant agent during preoperative chemoradiation for rectal cancer. Br J Cancer. 2015. Sep, pp. 1–7.

14. Pantziarka P, et al. Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent. ecancer. 2014;8:485.

15. Forget P, et al. Perioperative ketorolac in high risk breast cancer patients. Rationale, feasibility and methodology of a prospective randomized placebo-controlled trial. Med Hypotheses. 2013;81(4):707–12. doi: 10.1016/j.mehy.2013.07.033.

16. Lonnroth C, et al. Preoperative low dose NSAID treatment influences the genes for stemness, growth, invasion and metastasis in colorectal cancer. Int J Oncol. 2014 Dec;45(6):2208-20.