[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer <i>in vivo</i>

Abstract

// Ana Carolina B.M. Martin 1, * , Angelina M. Fuzer 1, * , Amanda B. Becceneri 1 , James Almada da Silva 2 , Rebeka Tomasin 1 , Delphine Denoyer 3 , Soo-Hyun Kim 4 , Katherine A. McIntyre 5 , Helen B. Pearson 6 , Belinda Yeo 7 , Aadya Nagpal 7 , Xiawei Ling 4 , Heloisa S. Selistre-de-Ara&uacute;jo 8 , Paulo C&eacute;zar Vieira 2 , Marcia R. Cominetti 1, * and Normand Pouliot 4, 5, 7, * 1 Department of Gerontology, Federal University of S&atilde;o Carlos, S&atilde;o Carlos, SP, Brazil 2 Department of Chemistry, Federal University of S&atilde;o Carlos, S&atilde;o Carlos, SP, Brazil 3 Metals in Medicine Laboratory, Centre for Cellular and Molecular Biology (CCMB), Melbourne Burwood Campus, Deakin University, VIC, Australia 4 Department of Pathology and University of Melbourne, VIC, Australia 5 Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia 6 European Cancer Stem Cell Research Institute, Cardiff University, Cathays, Cardiff, UK 7 Matrix Microenvironment and Metastasis Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, Australia 8 Department of Physiological Sciences, Federal University of S&atilde;o Carlos, S&atilde;o Carlos, SP, Brazil * Authors contributed equally to this work and share co-senior authorship Correspondence to: Marcia R. Cominetti, email: [e-mail] Keywords: gingerol, breast cancer, cell cycle, apoptosis, animal models Received: January 23, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: July 29, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: August 10, 2017 ABSTRACT 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 [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo . We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro . In addition, [10]-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 [10]-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 [10]-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.