Anticancer and Antimalarial Efficacy and Safety of Artemisinin-Derived Trioxane Dimers in Rodents

Posner, Gary H.; McRiner, Andrew J.; Paik, † Ik-Hyeon; Sur, Surojit; Borstnik, Kristina; Xie, Suji; Shapiro, Theresa A.; Alagbala, and Adebusola; Foster, Barbara A.

doi:10.1021/jm0303711

Cited by 114 publications

(104 citation statements)

References 13 publications

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“…* To whom correspondence should be addressed. tives) [1][2][3] . However, the traditional trial-and-error methods used to identify active compounds from numerous herbal compounds in TCM are time-consuming and labor intensive.…”

Section: Introductionmentioning

confidence: 99%

Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach

et al. 2016

Acta Pharmacol Sin

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Aim: Nuciferine is an aporphine alkaloid extracted from lotus leaves, which is a raw material in Chinese medicinal herb for weight loss. In this study we used a network pharmacology approach to identify the anti-tumor activity of nuciferine and the underlying mechanisms. Methods: The pharmacological activities and mechanisms of nuciferine were identified through target profile prediction, clustering analysis and functional enrichment analysis using our traditional Chinese medicine (TCM) network pharmacology platform. The antitumor activity of nuciferine was validated by in vitro and in vivo experiments. The anti-tumor mechanisms of nuciferine were predicted through network target analysis and verified by in vitro experiments. Results: The nuciferine target profile was enriched with signaling pathways and biological functions, including "regulation of lipase activity", "response to nicotine" and "regulation of cell proliferation". Target profile clustering results suggested that nuciferine to exert anti-tumor effect. In experimental validation, nuciferine (0.8 mg/mL) markedly inhibited the viability of human neuroblastoma SY5Y cells and mouse colorectal cancer CT26 cells in vitro, and nuciferine (0.05 mg/mL) significantly suppressed the invasion of 6 cancer cell lines in vitro. Intraperitoneal injection of nuciferine (9.5 mg/mL, ip, 3 times a week for 3 weeks) significantly decreased the weight of SY5Y and CT26 tumor xenografts in nude mice. Network target analysis and experimental validation in SY5Y and CT26 cells showed that the anti-tumor effect of nuciferine was mediated through inhibiting the PI3K-AKT signaling pathway and IL-1 levels in SY5Y and CT26 cells. Conclusion: By using a TCM network pharmacology method, nuciferine is identified as an anti-tumor agent against human neuroblastoma and mouse colorectal cancer in vitro and in vivo, through inhibiting the PI3K-AKT signaling pathways and IL-1 levels.

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Section: Introductionmentioning

confidence: 99%

Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach

et al. 2016

Acta Pharmacol Sin

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“…14 The observation that ART inhibits the growth of many transformed cell lines has led to the hypothesis that the drug can also be useful for the treatment of human neoplasia. [15][16][17][18][19][20][21][22][23][24] As shown by us and others, [25][26][27][28][29][30][31][32] ARSs reveal antiangiogenic features in vitro and in vivo. The molecular determinants of the antiangiogenic activity of ARSs are incompletely understood at present.…”

Section: Introductionmentioning

confidence: 99%

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

et al. 2006

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Artemisinin (ARS) and its derivatives are used for the second-line therapy of malaria infections with Plasmodium falciparum and P. vivax. ARSs also reveal profound antitumor activity in vitro and in vivo. In the present investigation, we correlated the mRNA expression data of 89 angiogenesis-related genes obtained by microarray hybridization from the database of the US National Cancer Institute with the 50% growth inhibition concentration values for eight ARSs (ARS, arteether (ARE), artesunate (ART), artemisetene, arteanuine B, dihydroartemisinylester stereoisomers 1 and 2). The constitutive expression of 30 genes correlated significantly with the cellular response to ARSs. By means of hierarchical cluster analysis and cluster image mapping expression, profiles were identified that determined significantly the cellular response to ART, ARE, artemether and dihydroartemisinylester stereoisomer 1. We have exemplarily validated the microarray data of six out of these 30 genes by realtime RT-PCR in seven cell lines. The fact that sensitivity and resistance of tumor cells could be predicted by the mRNA expression of angiogenesisrelated genes indicate that ARSs reveal their antitumor effects at least in part by inhibition of tumor angiogenesis. As many chemopreventive drugs exert antiangiogenic features, ARSs might also be chemopreventive in addition to their cytotoxic effects.

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“…Dihydroartemisinin peaked in the blood (0.7 μg/mL) at 12 h, and decreased to 0.18 μg/mL at 24 h. After 24 h, artemisinin concentration in feces was 2.4 μg/g, indicating artemisinin's poor bioavailability in goats when provided orally and as capsules. Posner et al (2004) observed high time-dependent first-pass metabolism in the gut and liver, this drug are conjugates such as glucuronides and can be eliminated through phase-II metabolism. Therefore, artemisinin has low water solubility, resulting in poor and erratic absorption upon oral administration, so the artemisinin conjugation reactions and hydrolysis are the principal reasons these derivatives have a short half-life.…”

Section: Discussionmentioning

confidence: 99%

Anthelmintic activity of Artemisia annua in sheep-model

Silva¹,

MagalhÃ£es²,

Sousa³

et al. 2017

J. Med. Plants Res.

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Artemisia annua L. is a well-known source of artemisinin, an antimalarial drug. This compound has been used in traditional medicine to treat malaria for many years. The anthelmintic property of A. annua has also been attributed to artemisinin, hence the belief that artemisinin could be useful as an alternative anthelmintic to control Haemonchus contortus in livestock. The present study focused on evaluating the anthelmintic activity of A. annua against H. contortus by oral administration on infected sheep in a controlled clinical trial. The trial was conducted using 24 male sheep of the Santa Inês breed, with average weight of 20 kg, artificially infected with H. contortus (Embrapa 2010 isolate). The animals were kept in metabolic cages and randomly divided into four homogeneous groups with six animals each, being: (T1) negative control (untreated), (T2) positive control: 10 mg/kg BW of levamisole phosphate, (T3) fed 10% A. annua (0.2% BW), (T4) fed 20% A. annua (0.4% BW). EPG counts were conducted on days -3, -2, -1, 0 (treatment day), 3, 7, 10, 14, 17, 21, 24 and 28 post-treatment. After extraction of the artemisinin in plant material, it was quantified in triplicate and analyzed by highperformance liquid chromatography with infrared detection. The average efficacy in the positive control treated with levamisole was 89%. Moderate anthelmintic efficacy against H. contortus was observed in the groups fed 0.2 and 0.4% BW A. annua for 30 days (32.9 and 14.8%, respectively), mainly from day 21 post treatment (47.1 and 25.2%, respectively). At the highest dose, the animals avoided eating due to the compound's bitter taste. It is concluded that A. annua presents moderate anthelmintic activity in sheep in both doses. The lowest dose was accepted by animals and seems to have practical use. Oral administration was safe and after further in vivo trials could be introduced in organic farms in tropical countries.

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Anticancer and Antimalarial Efficacy and Safety of Artemisinin-Derived Trioxane Dimers in Rodents

Cited by 114 publications

References 13 publications

Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach

Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

Anthelmintic activity of Artemisia annua in sheep-model

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