title: A mitochondria-targeting artemisinin derivative with sharply increased antitumor but depressed anti-yeast and anti-malaria activities.
abstract: The potent anti-malarial drug artemisinins are additionally anti-tumorigenic and inhibitory to yeast growth. The action mechanism of artemisinins, however, is not well understood. Heme and mitochondrial membrane are both suggested to be involved in the action of artemisinins. Because heme is also synthesized in the mitochondrion, mitochondria appear to be a critical organelle for artemisinins' activities. In this study, we synthesized a mitochondria-targeting artemisinin derivative by conjugating triphenylphosphonium (TPP) to artelinic acid (ARTa). ARTa-TPP displays far more potent anti-tumorigenic activity than its parent compound. In contrast, ARTa-TPP is much less active against yeast respiration growth and malarial parasites. Notably, ARTa-TPP is also associated with increased toxicity to other kinds of control mammalian cells. These results suggest divergent action modes for artemisinins against cancer cells and malaria or yeast cells. We conclude that mitochondrial targeting could substantially elevate the anticancer potency of artemisinins, but the accompanied increased toxicity to normal cells raises an alert. The mechanism regarding the opposing effects of TPP conjugation to ARTa on its anticancer and anti-malarial/anti-yeast potencies is discussed based on our current understandings of artemisinins' action.
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006418:Heme / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D006418:Heme