artemisinin

The origins

The history of artemisin and its potential therapeutic effects begins on May 23, 1967, when in China the National Executive Group on the search for antimalarial drugs, enrolling over 600 institutes, started a massive screening to identify new active ingredients with anti-parasitic activity.

Figure: Artemisin chemical structure

Only a few years later, around 1972, starting from a plant traditionally used in Chinese medicine - namely Artemisia annua - artemisin was identified. It was discovered that this active principle, with its complex chemical structure, is able to exert an antimalarial action even on drug-resistant parasites.

In 1976 the various studies made it possible to clarify the main mechanism of action of Artemisin . In particular, this oxygenated sesquiterpene, thanks to its particular endoperoxidic structure, would be able to interact with the Iron ion, forming free radicals and leading to the death of the cell due to oxidative shock.

The high concentration of iron in malarial plasmodia would thus justify the particular susceptibility of these parasites to the action of artemisin.

PLEASE NOTE: Artemisin is also known as qinghaosu .

Therapeutic Perspectives

Even tumor cells present large intracellular iron ion concentrations, combined with a high number of transmembrane receptors for transferrin (necessary for capturing extracellular iron and transporting it into the cell).

The iron ion is in fact necessary to support the exacerbated rate of mitotic division that distinguishes neoplastic cells. Not surprisingly, transmembrane receptor concentrations for transferrin correlate perfectly with tumor aggressiveness.

Due to the important iron concentrations, malignant cells are theoretically more sensitive to the pro-oxidant effect of artemisin, making it in fact quite selective.

On the basis of these evidences and these assumptions, for some years we have begun to experiment the use of Artemisin and its more selective derivatives, such as Artesunato and Diidroartemisina (DHA), in the oncology field.

To date, therefore, the main therapeutic promises of these active ingredients remain precisely those relating to oncological and immunological pathologies.

Antitumor mechanisms of action

The enormous impulse that the research has had on the antitumor effects of artemisin, underlined by the growing number of studies published in this regard, has allowed us to hypothesize, and in some cases to confirm through molecular models, different potential mechanisms of action of this active principle

Currently, the antitumor properties of artemisin and its derivatives appear to be supported by:

antiproliferative activity : able to regulate the unbalanced activity of the replicative cycle that characterizes cancer cells. In particular, these active principles would seem to control the expression of the cyclins, and of the related kinases, involved in the progress of the proliferative process.
All this, therefore, would result in a halt in cell proliferation.
A proapoptotic activity: as observed in several carcinoma cell lines. More precisely, artemisin, especially if used at high dosages, could induce the activation of pro-apoptotic factors, determining the activation of biological mechanisms involved in DNA fragmentation and consequent cell death.
An antimetastatic activity : important above all for the micro-metastases originated in the first phases of tumor development. This type of action would seem related to the ability of the artemisin to inhibit the expression of metalloproteases and other proteins, belonging to the integrin family, involved in the adhesion of the tumor cell to the extracellular matrix.
An antiangiogenic activity: from initial experimental evidence, artemisin's ability to inhibit the expression of factors such as VEGF and FGF, classically involved in the phenomenon of angiogenesis, emerges. More precisely, these factors would facilitate the formation of intra and peritumoral vascular structures, necessary to nourish the tumor mass as well as to facilitate the diffusion of neoplastic clones by blood.
An activity of chemotherapeutic support: interesting evidences have shown how the addition of artemisin and its derivatives to the classic chemotherapy, can enhance the cytotoxic tumor effect of the treatment, especially in case of inadequately responsive diseases or unfortunately drug-induced tumors resistant. However, the mechanisms of action of this activity have not yet been clarified.

Studies

Despite the fact that most of the studies in this regard are still experimental, therefore conducted mostly on cell lines or animal models, to date the data are particularly promising, thanks also to a fairly reproducible mechanism of action.

In vitro tests : several papers have demonstrated the cytotoxic activity of artemisin and its derivatives on cell lines of mastocytoma and murine renal adenocarcinoma.

More precisely, the 72 h incubation of these cell lines with artemisinine resulted in an inhibition of 70 - 90% of their proliferation, through the induction of the apoptotic process and the arrest of the cell cycle, as evidenced by works of molecular medicine.

Great effect was also achieved by associating artemisin with the classic cytotoxic and chemotherapeutic drugs, classically used in the therapeutic field.

In the wake of these studies, the National Cancer Institute's Therapeutic Development Program has observed the inhibitory efficacy of artemisin and its semisynthetic derivatives even against cell lines of colon, breast, ovarian, and central nervous system carcinoma, pancreas, lung, and against melanoma and Leukemia.

In vivo tests - experimental models: the successes of in vitro studies have led researchers involved in the fight against cancer to test the efficacy of Artemisin and its derivatives also in experimental models of animal cancer.

In these studies, mostly conducted on solid tumors, it was observed that the intake of artemisin could significantly slow down the exponential growth of the tumor, thus leading not only to an overall improvement of the clinical picture, but also to a significant reduction in mortality .

Clinical trials: artemisin and its derivatives have also been used in human clinical trials and in single clinical cases. Interesting successes have been observed for squamous cell carcinoma of the larynx, for pituitary macroadenoma and for some forms of lung cancer.

In all these studies, the aforementioned active ingredients have been added to the classic chemotherapy.

Many studies are still in progress to understand the real clinical potential of these derivatives.

Artemisin toxicity

Although long-term studies do not yet exist, therefore able to verify the potential toxic effects related to the therapeutic use of artemisin, the first experimental studies show, at particularly high dosages, predominantly neurotoxic effects.

However, referring to the studies published in the literature concerning the use of artemisin as an antimalarial, this active ingredient seems well tolerated at standard dosages.

Future applications

Artemisin has already been recommended for years for the sensitive antimalarial action.

However, this active principle has recently proved to be quite effective above all due to its strong cytostatic and cytotoxic potential.

Experimental studies have shown the high antitumor efficacy of artemisin and its derivatives, being able to offer a further therapeutic alternative to clinicians, especially against tumors that are particularly aggressive or inadequately responsive to therapy.

The entire scientific landscape, based on these promising studies, hopes that the different clinical trials currently in place can validate the therapeutic hypotheses carried out, thus expanding the potential therapeutic choices in favor of the doctor for the fight against cancer.