Molecular Pharmacology and Pharmacogenomics of Artemisinin and its Derivatives in Cancer Cells

Abstract

Secondary metabolites from plants can serve as defense against herbivores, microbes, viruses or competing plants. Many compounds from medicinal plants have pharmacological activities and thus may be a source for novel anti-tumor agents. We have analyzed natural products from traditional Chinese medicine during the past decade and focused our interest on the compound artemisinin from Artemisia annua L. (qinghao, sweet wormwood) and its derivatives. In addition to their anti-malarial properties, artemisinins are cytotoxic for cancer cells. The present review focuses on the mechanisms of action of artemisinins in cancer cells relating to: 1. anti-proliferative and anti-angiogenic effects, 2. induction of apoptosis, 3. oxidative stress, 4. oncogenes and tumor suppressor genes, and 5. multidrug resistance. Data on putative target molecules of artemisinins are presented and discussed, e.g. the translationally controlled tumor protein (TCTP). Emphasis is given to pharmacogenomic approaches to analyze the pleiotropic nature of mechanisms of artemisinins in cancer cells.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…Instrumental in this was the experimental 'tumour reversion model' developed by the Telerman group (Telerman and Amson 2009;Tuynder et al 2002Tuynder et al , 2004. Naturally, the cancer aspect of TCTP's 'function' has recently attracted increasing attention, as documented by the about 40 papers and 6 review articles (Telerman and Amson 2009;Bommer 2012;Acunzo et al 2014;Amson et al 2013Amson et al , 2011Chan et al 2012a;Efferth 2006;Koziol and Gurdon 2012) on 'TCTP and cancer' that appeared only within the last 10 years.…”

“…Given the well-established role of TCTP in cancer as summarised in this section, it is not surprising that the idea of exploring TCTP as an anticancer target protein is not new, and this interesting topic has already been covered in six review articles (Telerman and Amson 2009;Bommer 2012;Acunzo et al 2014;Amson et al 2013;Efferth 2005Efferth , 2006. Here I will briefly summarise these efforts, according to the groups of drugs investigated to target TCTP:…”

“…Artemisinin: Since the early discovery that TCTP of Plasmodium falciparum is a target protein of the antimalarial drug artemisinin (Bhisutthibhan et al 1998), this drug interaction has been studied in more detail (Chae et al 2006). Artemisinin not only displays antimalarial activity but was also found to be a potent anticancer agent in cellular assay (review in Efferth 2005), and screening for potential targets in this context has confirmed that TCTP is indeed a target for this drug (Efferth 2005(Efferth , 2006. The interaction of artemisinin with TCTP was then studied in cancer cells, and it was found that drug treatment results in degradation of TCTP (fortilin) via the ubiquitin-proteasome pathway (Fujita et al 2008).…”

Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway

“…ROS and carbon-centered radicals also contribute to the potent cytotoxic effects of artemisinin and derivatives on tumor cell lines in vitro (4)(5)(6)(7). Cytotoxic efficacy of these agents was increased by the addition of iron(II) salts alone and in combination with transferrin in vitro (8) and in vivo (9).…”

Cellular Function and Regulation of the Translationally Controlled Tumour Protein TCTP

“…The same group reported later that dehydroartemisinin (DHA), an important anti-malarial drug, which was previously shown to bind to Plasmodium falciparum TCTP, binds to and destabilises human TCTP in a proteasome-dependent manner [86]. This is interesting, since DHA is also considered an anti-cancer agent [85,108]. Although the reports on regulated protein degradation of TCTP are limited and anecdotal so far, it appears that this type of regulation may occur in a distinct cell cycle phase and under pro-apoptotic cell stress conditions.…”