Two distinct and competitive pathways confer the cellcidal actions of artemisinins

Abstract

The biological actions of artemisinin (ART), an antimalarial drug derived from Artemisia annua, remain poorly understood and controversial. Besides potent antimalarial activity, some of artemisinin derivatives (together with artemisinin, hereafter referred to as ARTs), in particular dihydroartemisinin (DHA), are also associated with anticancer and other antiparasitic activities. In this study, we used baker’s yeast Saccharomyces cerevisiae as cellular and genetic model to investigate the molecular and cellular properties of ARTs. Two clearly separable pathways exist. While all ARTs exhibit potent anti-mitochondrial actions as shown before, DHA exerts an additional strong heme-dependent, likely mitochondria-independent inhibitory action. More importantly, heme antagonizes the mitochondria-dependent cellcidal action. Indeed, when heme synthesis was inhibited, the mitochondria-dependent cellcidal action of ARTs could be dramatically strengthened, and significant yeast growth inhibition at as low as 100 nM ART, an increase of about 25 folds in sensitivity, was observed. We conclude that ARTs are endowed with two major and distinct types of properties: a potent and specific mitochondria-dependent reaction and a more general and less specific heme-mediated reaction. The competitive nature of these two actions could be explained by their shared source of the consumable ARTs, so that inhibition of the heme-mediated degradation pathway would enable more ARTs to be available for the mitochondrial action. These properties of ARTs can be used to interpret the divergent antimalarial and anticancer actions of ARTs.

A mitochondria-targeting artemisinin derivative with sharply increased antitumor but depressed anti-yeast and anti-malaria activities

“…It has been shown that the respiratory growth (i.e., on non-fermentable media) of yeast is especially sensitive to artemisinins2324. On fermentable media, yeast is much less sensitive to artemisinins26. The former inhibition is attributed to a partial mitochondrial membrane depolarization and the latter a relatively general, and mostly heme-mediated toxicity26.…”

“…On fermentable media, yeast is much less sensitive to artemisinins26. The former inhibition is attributed to a partial mitochondrial membrane depolarization and the latter a relatively general, and mostly heme-mediated toxicity26. We asked what effects of the mitochondria-targeting will have on these activities.…”

“…Later studies demonstrated two major types of activities of artemisinins in the yeast2526. One involves depolarization of mitochondrial membrane potential, and the other a heme-mediated cytotoxicity.…”

“…In fact, down-regulation of heme dramatically mitigates the heme-mediated cytotoxicity of DHA, but significantly increases the anti-mitochondrial potency of DHA and artemisinins. We proposed that the relatively specific anti-mitochondrial action and the less specific or general heme-mediated action of artemsinins may be competitive so that inhibition of the heme-mediated reaction makes more artemisinins available to act against the mitochondrial membrane26. For some mysterious reason hitherto unknown, mammalian mitochondrial membrane does not respond to artemisinins whereas those of malarial parasites and the yeast are highly sensitive24.…”

Artemisinin (Qinghaosu): a mesmerizing drug that still puzzles

“…We do not know yet what causes these differences but are actively working to unravel this mystery. Regarding the role of heme, we found when reacting with artemisinins, it appears to exert a general damaging effect on the cell, much less potent as well as less specific than the mitochondrial membrane depolarizing action of artemisinins [9]. These two different actions can be utilized to explain respectively the different properties of artemisinins against malarial parasites and cancer cells: one is very robust and selective, via membrane depolarization, whereas the other one, mediated by heme, is more general and much less potent.…”