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Cytotoxic effects of the anthraquinone derivatives 1′-deoxyrhodoptilometrin and (S)-(−)-rhodoptilometrin isolated from the marine echinoderm Comanthus sp.

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Abstract

We investigated cytotoxic effects of the anthraquinone derivatives 1′-deoxyrhodoptilometrin (SE11) and (S)-(−)-rhodoptilometrin (SE16) isolated from the marine echinoderm Comanthus sp. in two tumor cell lines (C6 glioma, Hct116 colon carcinoma). Both compounds showed cytotoxic effects, with SE11 [IC50-value (MTT assay): 13.1 µM in Hct116 cells] showing a higher potency to induce apoptotic and necrotic cell death. No generation of oxidative stress was detectable (DCF assay), and also no modulation of Nrf2/ARE and NFκB signaling could be shown. Investigation of 23 protein kinases associated with cell proliferation, survival, metastasis, and angiogenesis showed that both compounds were potent inhibitors of distinct kinases, e.g., IGF1-receptor kinase, focal adhesion kinase, and EGF receptor kinase with SE11 being a more potent compound (IC50 values: 5, 18.4 and 4 µM, respectively). SE11 caused a decrease in ERK phosphorylation which may be a consequence of the inhibition of EGF receptor kinase by this compound. Since an inhibition of the EGF receptor/MAPK pathway is an important target for diverse cytostatic drugs, we suggest that the anthraquinone derivative 1′-deoxyrhodoptilometrin (SE11) may be an interesting lead structure for the development of new anticancer drugs.

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Abbreviations

ARE:

Antioxidant responsive element

DCF:

Dichlorofluorescein

DPPH:

1,1-Diphenyl-2-picrylhydrazyl

ERK:

Extracellular-regulated protein kinase

FBS:

Fetal bovine serum

HO-1:

Heme oxigenase

LDH:

Lactate dehydrognase

MTT:

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium-bromide

SEAP:

Secreted embryonic alkaline phosphatase

TNF-α:

Tumor necrosis factor α

SE11:

1′-Deoxyrhodoptilometrin

SE16:

(S)-(−)-Rhodoptilometrin

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Acknowledgments

The authors acknowledge Dr. R. A. Edrada-Ebel (University of Strathclyde, Glasgow, UK) for supplying the echinoderm specimen and HRESI mass spectrometry. We would like to thank Dr. N. J. de Voogd (National Museum of Natural History, Leiden, Netherlands) for taxonomical classification. We are also indebted to Dr. V. Wray (Helmholtz Center for Infection Research, Braunschweig, Germany) for providing the necessary NMR spectral analysis. We thank the Egyptian Government for the predoctoral scholarship (S.E.).

Author contributions

W.W. and P.P. conceived and designed the experiments; S.E., A.B., Y.C., F.T., H.K., and W.L. performed the experiments, S.E., A.B., Y.C., F.T., H.K., and W.L. analyzed the data; W.W. and P.P. wrote the paper.

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Authors and Affiliations

  1. Biofunctionality of Secondary Plant Compounds, Institute of Agricultural and Nutritional Sciences, Martin-Luther-Universität Halle-Wittenberg, Weinbergweg 22, 06120, Halle/Saale, Germany

    Wim Wätjen

  2. Institute of Toxicology, Heinrich-Heine-Universität, P.O. Box 101007, 40001, Düsseldorf, Germany

    Wim Wätjen, Anja Bergermann & Yvonni Chovolou

  3. Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-Universität, Universitätsstr. 1, 40225, Düsseldorf, Germany

    Sherif S. Ebada & Peter Proksch

  4. ProQinase GmbH, Breisacher Str. 117, 79106, Freiburg, Germany

    Frank Totzke & Michael H. G. Kubbutat

  5. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China

    Wenhan Lin

  6. Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street 1, Cairo, 11566, Egypt

    Sherif S. Ebada

Authors
  1. Wim Wätjen
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  6. Michael H. G. Kubbutat
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Correspondence to Wim Wätjen.

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Wätjen, W., Ebada, S.S., Bergermann, A. et al. Cytotoxic effects of the anthraquinone derivatives 1′-deoxyrhodoptilometrin and (S)-(−)-rhodoptilometrin isolated from the marine echinoderm Comanthus sp.. Arch Toxicol 91, 1485–1495 (2017). https://doi.org/10.1007/s00204-016-1787-7

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