-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo
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Ana Carolina B.M. Martin1,*, Angelina M. Fuzer1,*, Amanda B. Becceneri1, James Almada da Silva2, Rebeka Tomasin1, Delphine Denoyer3, Soo-Hyun Kim4, Katherine A. McIntyre5, Helen B. Pearson6, Belinda Yeo7, Aadya Nagpal7, Xiawei Ling4, Heloisa S. Selistre-de-Araújo8, Paulo Cézar Vieira2, Marcia R. Cominetti1,* and Normand Pouliot4,5,7,*
1Department of Gerontology, Federal University of São Carlos, São Carlos, SP, Brazil
2Department of Chemistry, Federal University of São Carlos, São Carlos, SP, Brazil
3Metals in Medicine Laboratory, Centre for Cellular and Molecular Biology (CCMB), Melbourne Burwood Campus, Deakin University, VIC, Australia
4Department of Pathology and University of Melbourne, VIC, Australia
5Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia
6European Cancer Stem Cell Research Institute, Cardiff University, Cathays, Cardiff, UK
7Matrix Microenvironment and Metastasis Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, Australia
8Department of Physiological Sciences, Federal University of São Carlos, São Carlos, SP, Brazil
*Authors contributed equally to this work and share co-senior authorship
Marcia R. Cominetti, email: [email protected]
Keywords: gingerol, breast cancer, cell cycle, apoptosis, animal models
Received: January 23, 2017 Accepted: July 29, 2017 Published: August 10, 2017
There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin (Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of -gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo. We show that -gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro. In addition, -gingerol is well tolerated in vivo, induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that -gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that -gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients.
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