Abstract
Artemisia annua is currently the only commercial source of the sesquiterpene lactone artemisinin. Since artemisinin was discovered as the active component of A. annua in early 1970s, hundreds of papers have focused on the anti-parasitic effects of artemisinin and its semi-synthetic analogs dihydroartemisinin, artemether, arteether, and artesunate. Artemisinin per se has not been used in mainstream clinical practice due to its poor bioavailability when compared to its analogs. In the past decade, the work with artemisinin-based compounds has expanded to their anti-cancer properties. Although artemisinin is a major bioactive component present in the traditional Chinese herbal preparations (tea), leaf flavonoids, also present in the tea, have shown a variety of biological activities and may synergize the effects of artemisinin against malaria and cancer. However, only a few studies have focused on the potential synergistic effects between flavonoids and artemisinin. The resurgent idea that multi-component drug therapy might be better than monotherapy is illustrated by the recent resolution of the World Health Organization to support artemisinin-based combination therapies (ACT), instead of the previously used monotherapy with artemisinins. In this critical review we will discuss the possibility that artemisinin and its semi-synthetic analogs might become more effective to treat parasitic diseases (such as malaria) and cancer if simultaneously delivered with flavonoids. The flavonoids present in A. annua leaves have been linked to suppression of CYP450 enzymes responsible for altering the absorption and metabolism of artemisinin in the body, but also have been linked to a beneficial immunomodulatory activity in subjects afflicted with parasitic and chronic diseases.
Highlights
A brief search through PubMed, on March 2010, using the keywords “artemisinin” and “malaria”returned 1,266 hits, while using “Artemisia annua” and “flavonoids” returned 12 hits, but “artemisia flavonoids” and “Artemisia annua flavonoids” combined with “malaria” returned only four and two hits, respectively
For the flavonoids to exert their putative role as oxidative stress modulators, antimalarial, anticancer, or synergistic effects, they are required to be absorbed from the gastrointestinal tract
We could not find any studies where the combination of a group of flavonoids, specific flavonoids, or at least a crude plant extract was tested in combination with an antimalarial or anticancer drug in vivo, recent evidence is that common dietary flavonoids such as quercetin, apigenin, luteolin, and kaempferol had both individual and synergistic effects against Plasmodium falciparum in vitro [53]
Summary
A brief search through PubMed, on March 2010, using the keywords “artemisinin” and “malaria”. “artemisinin” and “cancer” returned 117 hits, “Artemisia flavonoids” and “cancer”, 12 hits, and “Artemisia annua flavonoids” and “cancer”, only one hit This search meant to establish that in the past 15 years there has been plenty of research on the activity of artemisinin against malaria, followed by less on cancer. This varying recrudescence is related to the short half-life of artemisinin, and to the duration of treatment and to the loss in sensitivity to dihydroartemisinin (the active blood metabolite) by different strains of Plasmodium, which is remediated by the combination of artemisinin with other antimalarial drugs of longer half-lives and different modes of action [11]. If there would be no biological activity or benefit for flavonoids, hydroxylated or methoxylated, glycosylated or not, why would plants go through such an energetically-expensive endeavor to produce so many different kinds of flavonoids?
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