The Antagonizing Role of Heme in the Antimalarial Function of Artemisinin: Elevating Intracellular Free Heme Negatively Impacts Artemisinin Activity in Plasmodium falciparum

被引:10
作者
Zhu, Pan [1 ]
Zhou, Bing [1 ,2 ]
机构
[1] Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China
[2] Chinese Acad Sci, Shenzhen Inst Synthet Biol, Shenzhen Inst Adv Technol, Shenzhen 518055, Peoples R China
关键词
heme; artemisinins; hemozoin; triarylimidazole; 14c; heme oxygenase; DRUG; MALARIA; RESISTANCE; HEMOGLOBIN; MECHANISM; IRON; EPIDEMIOLOGY; SENSITIVITY; QINGHAOSU; DYNAMICS;
D O I
10.3390/molecules27061755
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The rich source of heme within malarial parasites has been considered to underly the action specificity of artemisinin. We reasoned that increasing intraparasitic free heme levels might further sensitize the parasites to artemisinin. Various means, such as modulating heme synthesis, degradation, polymerization, or hemoglobin digestion, were tried to boost intracellular heme levels, and under several scenarios, free heme levels were significantly augmented. Interestingly, all results arrived at the same conclusion, i.e., elevating heme acted in a strongly negative way, impacting the antimalarial action of artemisinin, but exerted no effect on several other antimalarial drugs. Suppression of the elevated free heme level by introducing heme oxygenase expression effectively restored artemisinin potency. Consistently, zinc protoporphyrin IX/zinc mesoporphyrin, as analogues of heme, drastically increased free heme levels and, concomitantly, the EC50 values of artemisinin. We were unable to effectively mitigate free heme levels, possibly due to an unknown compensating heme uptake pathway, as evidenced by our observation of efficient uptake of a fluorescent heme homologue by the parasite. Our results thus indicate the existence of an effective and mutually compensating heme homeostasis network in the parasites, including an uncharacterized heme uptake pathway, to maintain a certain level of free heme and that augmentation of the free heme level negatively impacts the antimalarial action of artemisinin. Importance: It is commonly believed that heme is critical in activating the antimalarial action of artemisinins. In this work, we show that elevating free heme levels in the malarial parasites surprisingly negatively impacts the action of artemisinin. We tried to boost free heme levels with various means, such as by modulating heme synthesis, heme polymerization, hemoglobin degradation and using heme analogues. Whenever we saw elevation of free heme levels, reduction in artemisinin potency was also observed. The homeostasis of heme appears to be complex, as there exists an unidentified heme uptake pathway in the parasites, nullifying our attempts to effectively reduce intraparasitic free heme levels. Our results thus indicate that too much heme is not good for the antimalarial action of artemisinins. This research can help us better understand the biological properties of this mysterious drug.
引用
收藏
页数:15
相关论文
共 51 条
[41]   Two distinct and competitive pathways confer the cellcidal actions of artemisinins [J].
Sun, Chen ;
Li, Jian ;
Cao, Yu ;
Long, Gongbo ;
Zhou, Bing .
MICROBIAL CELL, 2015, 2 (01) :14-25
[42]   The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine [J].
Tu, Youyou .
NATURE MEDICINE, 2011, 17 (10) :1217-1220
[43]   Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum [J].
Wang, Jigang ;
Zhang, Chong-Jing ;
Chia, Wan Ni ;
Loh, Cheryl C. Y. ;
Li, Zhengjun ;
Lee, Yew Mun ;
He, Yingke ;
Yuan, Li-Xia ;
Lim, Teck Kwang ;
Liu, Min ;
Liew, Chin Xia ;
Lee, Yan Quan ;
Zhang, Jianbin ;
Lu, Nianci ;
Lim, Chwee Teck ;
Hua, Zi-Chun ;
Liu, Bin ;
Shen, Han-Ming ;
Tan, Kevin S. W. ;
Lin, Qingsong .
NATURE COMMUNICATIONS, 2015, 6
[44]   Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation [J].
Wang, Juan ;
Huang, Liying ;
Li, Jian ;
Fan, Qiangwang ;
Long, Yicheng ;
Li, Ying ;
Zhou, Bing .
PLOS ONE, 2010, 5 (03) :A158-A169
[45]  
WEI NM, 1994, BIOCHEM PHARMACOL, V48, P737, DOI 10.1016/0006-2952(94)90051-5
[46]  
WERNSDORFER WH, 1991, PHARMACOL THERAPEUT, V50, P95, DOI 10.1016/0163-7258(91)90074-V
[47]   Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against Plasmodium falciparum [J].
Wicht, Kathryn J. ;
Combrinck, Jill M. ;
Smith, Peter J. ;
Hunter, Roger ;
Egan, Timothy J. .
ACS MEDICINAL CHEMISTRY LETTERS, 2017, 8 (02) :201-205
[48]   Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies [J].
Witkowski, Benoit ;
Amaratunga, Chanaki ;
Khim, Nimol ;
Sreng, Sokunthea ;
Chim, Pheaktra ;
Kim, Saorin ;
Lim, Pharath ;
Mao, Sivanna ;
Sopha, Chantha ;
Sam, Baramey ;
Anderson, Jennifer M. ;
Duong, Socheat ;
Chuor, Char Meng ;
Taylor, Walter R. J. ;
Suon, Sella ;
Mercereau-Puijalon, Odile ;
Fairhurst, Rick M. ;
Menard, Didier .
LANCET INFECTIOUS DISEASES, 2013, 13 (12) :1043-1049
[49]   Epidemiology of drug-resistant malaria [J].
Wongsrichanalai, C ;
Pickard, AL ;
Wernsdorfer, WH ;
Meshnick, SR .
LANCET INFECTIOUS DISEASES, 2002, 2 (04) :209-218
[50]   Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins [J].
Xie, Stanley C. ;
Dogovski, Con ;
Hanssen, Eric ;
Chiu, Francis ;
Yang, Tuo ;
Crespo, Maria P. ;
Stafford, Che ;
Batinovic, Steven ;
Teguh, Silvia ;
Charman, Susan ;
Klonis, Nectarios ;
Tilley, Leann .
JOURNAL OF CELL SCIENCE, 2016, 129 (02) :406-416