Subcellular Localization of a Fluorescent Artemisinin Derivative to Endoplasmic Reticulum

Liu, Yungen; Lok, Chun‐Nam; Ko, Ben C.B.; Shum, Tina Yuen-Ting; Wong, Man Leung; Che, Chi‐Ming

doi:10.1021/ol902890j

Cited by 52 publications

(43 citation statements)

References 43 publications

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“…8,12,50–52 For example, depending on the experimental model, some drug derivatives concentrate in the endoplasmic reticulum while others localize in the mitochondrion. 51 It seems a consensus, based on the structure-function relationship of this class of compounds, 52 that artemisinins do not bind specific targets. Instead, the modification of protein function by artesunate, as might to be the case with Keap1, probably involves protein thiol residues and alkylation reactions.…”

Section: Discussionmentioning

confidence: 99%

Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells

Ravindra

Chang

et al. 2015

Chem. Res. Toxicol.

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The anti-malarial drug artesunate is a semi-synthetic derivative of artemisinin, the principal active component of a medicinal plant Artemisia annua. It is hypothesized to attenuate allergic asthma via inhibition of multiple signaling pathways. We used a comprehensive approach to elucidate the mechanism of action of artesunate by designing a novel biotinylated dihydroartemisinin (BDHA) to identify cellular protein targets of this anti-inflammatory drug. By adopting an untargeted proteomics approach, we demonstrated that artesunate may exert its protective anti-inflammatory effects via direct interaction with multiple proteins, most importantly with a number of mitochondrial enzymes related to glucose and energy metabolism, along with mRNA and gene expression, ribosomal regulation, stress responses and structural proteins. In addition, the modulatory effects of artesunate on various cellular transcription factors were investigated using a transcription factor array, which revealed that artesunate can simultaneously modulate multiple nuclear transcription factors related to several major pro- and anti-inflammatory signalling cascades in human bronchial epithelial cells. Artesunate significantly enhanced nuclear levels of nuclear factor erythroid-2-related factor 2 (Nrf2), a key promoter of antioxidant mechanisms, which is inhibited by the Kelch-like ECH-associated protein 1 (Keap1). Our results demonstrate that, like other electrophilic Nrf2 regulators, artesunate activates this system via direct molecular interaction/modification of Keap1, freeing Nrf2 for transcriptional activity. Altogether, the molecular interactions and modulation of nuclear transcription factors provide invaluable insights into the broad pharmacological actions of artesunate in inflammatory lung diseases and related inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells

Ravindra

Chang

et al. 2015

Chem. Res. Toxicol.

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“…Interestingly, a fluorescent artemisinin derivative ( 5 ), which showed around ten-fold more potent cytotoxicity toward the human hepatoma HepG2 cells than ART ( 1 ), was synthesized (Scheme 3 ). The subcellular localization of 5 in the human hepatoma Hep3B cells was investigated, which indicated that endoplasmic reticulum (ER) rather than mitochondria is the major locating site of 5 (Scheme 3 ) [49]. This provides an important clue for the future characterization of the molecular target of ART and its analogues for their antitumor activity.…”

Section: Characterization Of Artemisinin: From An Antimalarial Drumentioning

confidence: 99%

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones

Ren¹,

Yu²,

Kinghorn

2016

CMC

136

121

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Sesquiterpene lactones are of considerable interest due to their potent bioactivities, including cancer cell cytotoxicity and antineoplastic efficacy in in vivo studies. Among these compounds, artesunate, dimethylaminoparthenolide, and L12ADT peptide prodrug, a derivative of thapsigargin, are being evaluated in current cancer clinical or preclinical trials. Based on the structures of several antitumor sesquiterpene lactones, a number of analogues showing greater potency have been either isolated as natural products or partially synthesized, and some potential anticancer agents that have emerged from this group of lead compounds have been investigated extensively. The present review focuses on artemisinin, parthenolide, thapsigargin, and their naturally occurring or synthetic analogues showing potential anticancer activity. This provides an overview of the advances in the development of these types of sesquiterpene lactones as potential anticancer agents, including their structural characterization, synthesis and synthetic modification, and antitumor potential, with the mechanism of action and structure-activity relationships also discussed. It is hoped that this will be helpful in stimulating the further interest in developing sesquiterpene lactones and their derivatives as new anticancer agents.

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“…In fact, thapsigargin lacks the endoperoxide moiety and only generates discrete ROS levels. Nevertheless the ER appears to be a relevant site for artemisinin action as in HepG2 cells a fluorescent derivative has been shown to preferentially accumulate in this cell compartment [60]. …”

Section: Antitumor Mechanism Of Action Of Artemisininmentioning

confidence: 99%

Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug

Crespo-Ortiz

Wei

2012

Journal of Biomedicine and Biotechnology

324

267

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Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells. Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity. In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis. In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression. However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects. The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated. The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents.

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Subcellular Localization of a Fluorescent Artemisinin Derivative to Endoplasmic Reticulum

Cited by 52 publications

References 43 publications

Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells

Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones

Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug

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