Two distinct and competitive pathways confer the cellcidal actions of artemisinins
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 dihydroartemisin...
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Shared Science Publishers OG
2015-01-01
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| Series: | Microbial Cell |
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| Online Access: | http://microbialcell.com/researcharticles/two-distinct-and-competitive-pathways-confer-the-cellcidal-actions-of-artemisinins/ |
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| author | Chen Sun Jian Li Yu Cao Gongbo Long Bing Zhou |
| author_facet | Chen Sun Jian Li Yu Cao Gongbo Long Bing Zhou |
| author_sort | Chen Sun |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5a2f8783d5de48ba8f42033d00aeea42 |
| institution | DOAJ |
| issn | 2311-2638 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Shared Science Publishers OG |
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| series | Microbial Cell |
| spelling | doaj-art-5a2f8783d5de48ba8f42033d00aeea422025-08-20T02:53:20ZengShared Science Publishers OGMicrobial Cell2311-26382015-01-0121142510.15698/mic2015.01.181Two distinct and competitive pathways confer the cellcidal actions of artemisininsChen Sun0Jian Li1Yu Cao2Gongbo Long3Bing Zhou4These authors contribute equally to this work.These authors contribute equally to this work.State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China.State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China.State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China.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.http://microbialcell.com/researcharticles/two-distinct-and-competitive-pathways-confer-the-cellcidal-actions-of-artemisinins/hememitochondriaartemisininyeastcancer |
| spellingShingle | Chen Sun Jian Li Yu Cao Gongbo Long Bing Zhou Two distinct and competitive pathways confer the cellcidal actions of artemisinins Microbial Cell heme mitochondria artemisinin yeast cancer |
| title | Two distinct and competitive pathways confer the cellcidal actions of artemisinins |
| title_full | Two distinct and competitive pathways confer the cellcidal actions of artemisinins |
| title_fullStr | Two distinct and competitive pathways confer the cellcidal actions of artemisinins |
| title_full_unstemmed | Two distinct and competitive pathways confer the cellcidal actions of artemisinins |
| title_short | Two distinct and competitive pathways confer the cellcidal actions of artemisinins |
| title_sort | two distinct and competitive pathways confer the cellcidal actions of artemisinins |
| topic | heme mitochondria artemisinin yeast cancer |
| url | http://microbialcell.com/researcharticles/two-distinct-and-competitive-pathways-confer-the-cellcidal-actions-of-artemisinins/ |
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