Oncotarget

Research Papers:

Cytotoxic profiling of artesunic and betulinic acids and their synthetic hybrid compound on neurons and gliomas

Annemarie Ackermann, Aysun Çapcı Karagöz, Ali Ghoochani, Michael Buchfelder, Ilker Eyüpoglu, Svetlana B. Tsogoeva and Nicolai Savaskan _

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Oncotarget. 2017; 8:61457-61474. https://doi.org/10.18632/oncotarget.18390

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Abstract

Annemarie Ackermann1,*, Aysun Çapcı Karagöz2,*, Ali Ghoochani1, Michael Buchfelder3, Ilker Eyüpoglu1,3, Svetlana B. Tsogoeva2 and Nicolai Savaskan1,3,4

1Translational Cell Biology & Neurooncology Laboratory, Universitätsklinikum Medical School Erlangen, Friedrich-Alexander University of Erlangen – Nürnberg (FAU), Erlangen, Germany

2Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander University of Erlangen – Nürnberg (FAU), Erlangen, Germany

3Department of Neurosurgery, Universitätsklinikum Medical School Erlangen, Friedrich-Alexander University of Erlangen – Nürnberg (FAU), Erlangen, Germany

4BiMECON Ent., Berlin, Germany

*These authors have contributed equally to this work

Correspondence to:

Nicolai Savaskan, email: savaskan@gmx.net or nic.savaskan@gmail.com

Svetlana B. Tsogoeva, email: svetlana.tsogoeva@fau.de

Keywords: cell death, cancer cytotoxicity, artesunic acid, betulinic acid, hybrid synthesis

Received: October 11, 2016     Accepted: May 07, 2017     Published: June 07, 2017

ABSTRACT

Gliomas are brain-born tumors with devastating impact on their brain microenvironment. Novel approaches employ multiple combinations of chemical compounds in synthetic hybrid molecules to target malignant tumors. Here, we report on the chemical hybridization approach exemplified by artesunic acid (ARTA) and naturally occurring triterpene betulinic acid (BETA). Artemisinin derived semisynthetic compound artesunic acid (ARTA) and naturally occurring triterpene BETA were used to synthetically couple to the hybrid compound termed 212A. We investigated the impact of 212A and its parent compounds on glioma cells, astrocytes and neurons. ARTA and BETA showed cytotoxic effects on glioma cells at micromolar concentrations. ARTA was more effective on rodent glioma cells compared to BETA, whereas BETA exhibited higher toxic effects on human glioma cells compared to ARTA. We investigated these compounds on non-transformed glial cells and neurons as well. Noteworthy, ARTA showed almost no toxic effects on astrocytes and neurons, whereas BETA as well as 212A displayed neurotoxicity at higher concentrations. Hence we compared the efficacy of the hybrid 212A with the combinational treatment of its parent compounds ARTA and BETA. The hybrid 212A was efficient in killing glioma cells compared to single compound treatment strategies. Moreover, ARTA and the hybrid 212A displayed a significant cytotoxic impact on glioma cell migration. Taken together, these results demonstrate that both plant derived compounds ARTA and BETA operate gliomatoxic with minor neurotoxic side effects. Altogether, our proof-of-principle study demonstrates that the chemical hybrid synthesis is a valid approach for generating efficacious anti-cancer drugs out of virtually any given structure. Thus, synthetic hybrid therapeutics emerge as an innovative field for new chemotherapeutic developments with low neurotoxic profile.


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