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Quinones and halogenated monoterpenes of algal origin show anti-proliferative effects against breast cancer cells in vitro

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Summary

Red and brown algae have been shown to produce a variety of compounds with chemotherapeutic potential. A recent report described the isolation of a range of novel polyhalogenated monoterpene compounds from the red algae Plocamium corallorhiza and Plocamium cornutum collected off the coast of South Africa, together with the previously described tetraprenylquinone, sargaquinoic acid (SQA), from the brown algae Sargassum heterophyllum. In our study, the algal compounds were screened for anti-proliferative activity against metastatic MDA-MB-231 breast cancer cells revealing that a number of compounds displayed anti-cancer activity with IC50 values in the micromolar range. A subset of the compounds was tested for differential toxicity in the MCF-7/MCF12A system and five of these, including sargaquinoic acid, were found to be at least three times more toxic to the breast cancer than the non-malignant cell line. SQA was further analysed in terms of its mechanism of cytotoxicity in MDA-MB-231 cells. The ability to initiate apoptosis was distinguished from the induction of an inflammatory necrotic response via flow cytometry with propidium iodide and Hoescht staining, confocal microscopy with Annexin V and propidium iodide staining as well as the PARP cleavage assay. We report that SQA induced apoptosis while a polyhalogenated monoterpene RU015 induced necrosis in metastatic breast cancer cells in vitro. Furthermore, we demonstrated that apoptosis induction by SQA occurs via caspase-3, -6, -8, -9 and -13 and was associated with down-regulation of Bcl-2. In addition, cell cycle analyses revealed that the compound causes G1 arrest in MDA-MB-231 cells.

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Acknowledgements

This research was supported by grants from the Cancer Research Initiative of South Africa (CARISA) and the South African National Research Foundation (NRF). PhD Scholarships from Rhodes University (RU), the NRF and RU Henderson Foundation (JdlM) and Masters scholarships from the RU Henderson foundation, the German Academic Exchange Service (DAAD) and the Ernst and Ethel Eriksen trust (JCL) are hereby gratefully acknowledged.

Conflict of interest

The authors declare that they have no conflict of interest

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Authors and Affiliations

  1. The Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, P. O. Box 94, Grahamstown, 6140, South Africa

    Jo-Anne de la Mare, Jessica C. Lawson, Adrienne L. Edkins & Gregory L. Blatch

  2. Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa

    Maynard T. Chiwakata & Denzil R. Beukes

  3. School of Biomedical and Health Sciences, Faculty of Health, Engineering and Science, Victoria University, Melbourne, Victoria, Australia

    Gregory L. Blatch

Authors
  1. Jo-Anne de la Mare
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  2. Jessica C. Lawson
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  3. Maynard T. Chiwakata
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  4. Denzil R. Beukes
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  5. Adrienne L. Edkins
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  6. Gregory L. Blatch
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Corresponding author

Correspondence to Adrienne L. Edkins.

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Fig. S1

Kinetic study of the anti-proliferative effect of sargaquinoic acid against MDA-MB-231 cells. Cells were treated with 10, 40, 60, 80 and 100 μM of sargaquinoic acid over 24, 48, 72 or 96 h and their proliferative ability assessed by MTT assay. Percentage survival values were calculated relative to a DMSO vehicle-treated control. (JPEG 238 kb)

Fig. S2

Measurement of apoptotic cell death by flow cytometry in MDA-MB-231 cells. Treatment was with DMSO (vehicle control), paclitaxel or RU015 for 15 h, followed by staining with Hoescht 33342 and/or Propidium iodide (PI) and analysis by flow cytometry (a) Gating carried out on a forward- and side-scatter representation of the unstained vehicle-treated sample and copied to all subsequent samples. Assessment of degree of apoptosis upon treatment with a range of concentrations of either (b) paclitaxel or (c) RU015. (JPEG 263 kb)

Fig. S3

Cell cycle analysis by flow cytometry with propidium iodide staining. (a) Doublet discrimination to prevent false positives due to cell aggregates. Gating was carried out on an area (A) versus width (W) representation of the propidium iodide (PI)-stained DMSO vehicle-treated sample and copied to all subsequent samples. (b) Paclitaxel induces a G2-M phase arrest in MDA-MB-231 cells. Treatment was with either vehicle control (DMSO) or 50 nM paclitaxel (Ptx) for 16 h. Population gating was carried out according to the DMSO-treated control. (JPEG 177 kb)

Table S1

Pharmacological profiling of selected marine algal compounds using the Rule of 5 (Ro5) (DOC 28 kb)

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de la Mare, JA., Lawson, J.C., Chiwakata, M.T. et al. Quinones and halogenated monoterpenes of algal origin show anti-proliferative effects against breast cancer cells in vitro. Invest New Drugs 30, 2187–2200 (2012). https://doi.org/10.1007/s10637-011-9788-0

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  • DOI: https://doi.org/10.1007/s10637-011-9788-0

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