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Bioassay-guided isolation of cantharidin from blister beetles and its anticancer activity through inhibition of epidermal growth factor receptor-mediated STAT3 and Akt pathways

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Cantharidin is an active constituent of blister beetles (cantharides) which have traditionally been used for cancer treatment. Several studies have shown that cantharidin has a cytotoxic effect on various cancer cells. However, few studies have examined the effect of cantharidin on signal transducer and activator of transcription 3 (STAT3) signaling in cancer. In this study, we isolated cantharidin from cantharides by bioassay-guided fractionation and examined its inhibitory effect on STAT3 activation in human breast cancer MDA-MB-231 cells, expressing high level of phosphorylated STAT3. Cantharides were extracted with acetonitrile and separated into hexane, methylene chloride/acetonitrile, and water fractions. The methylene chloride/acetonitrile fraction was further separated into four fractions by preparative high-throughput high-performance liquid chromatography. Cantharidin was then isolated from the third fraction by countercurrent chromatography and structurally determined by comparing nuclear magnetic resonance and high-resolution mass spectrometry data. Cantharidin inhibited STAT3 tyrosine phosphorylation in MDA-MB-231 cells. Cantharidin suppressed epidermal growth factor (EGF)-induced STAT3 and PI3K/Akt signaling pathways through inhibition of EGF receptor phosphorylation. Moreover, cantharidin reduced cell proliferation and induced apoptosis with downregulation of STAT3 target genes, such as Bcl-2, COX-2, and cyclin D1. Taken together, this study provides evidence that cantharidin may be a potential therapeutic agent for triple-negative breast cancer by reducing EGFR-mediated STAT3 and Akt signaling pathways.

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Acknowledgements

This work was supported by an MRC grant from the National Research Foundation of Korea (No. 2009-0083533).

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  1. Jaemoo Chun and Min Kyoung Park contributed equally to this work.

Authors and Affiliations

  1. Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea

    Jaemoo Chun, Min Kyoung Park, Hyejin Ko & Yeong Shik Kim

  2. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Jaemoo Chun

  3. Department of Herbology, College of Korean Medicine, Kyung Hee University, Seoul, 02447, South Korea

    Kyungjin Lee

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  1. Jaemoo Chun
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  2. Min Kyoung Park
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Correspondence to Yeong Shik Kim.

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Chun, J., Park, M.K., Ko, H. et al. Bioassay-guided isolation of cantharidin from blister beetles and its anticancer activity through inhibition of epidermal growth factor receptor-mediated STAT3 and Akt pathways . J Nat Med 72, 937–945 (2018). https://doi.org/10.1007/s11418-018-1226-6

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