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Front. Pharmacol. | doi: 10.3389/fphar.2018.00070

Cardiac Glycoside Glucoevatromonoside Induces Cancer Type-specific Cell Death

 Naira F. Schneider1,  Claudia Cerella2,  Jin-Young Lee3,  Aloran Mazumder3, Kyung Rok Kim3, Annelise de Carvalho1,  Rodrigo M. Pádua4, Jennifer Munkert5, Wolfgang Kreis5, Kyu-Won Kim6, Christo Christov7, Hyun-Jung Kim8, Mario Dicato2, Byung-Woo Han3,  Fernao Braga4, Cláudia M. O. Simões1 and  Marc Diederich3*
  • 1Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina, Brazil
  • 2LBMCC, Fondation de Recherche Cancer et Sang, Luxembourg
  • 3Seoul National University, South Korea
  • 4Universidade Federal de Minas Gerais, Brazil
  • 5Department of Biology, Friedrich-Alexander Universität, Germany
  • 6SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, South Korea
  • 7Faculté de Médecine, Université de Lorraine, France
  • 8College of Pharmacy, Chung-Ang University, South Korea

Cardiac glycosides (CGs) are natural compounds used traditionally to treat congestive heart diseases. Recent investigations repositioned CGs as potential anticancer agents. To discover novel cytotoxic CG scaffolds, we selected the cardenolide glucoevatromonoside (GEV) out of 46 CGs for its low nanomolar anti-lung cancer activity. GEV presented reduced toxicity towards non-cancerous cell types (lung MRC-5 and PBMC) and high-affinity binding to the Na+/K+-ATPase alpha subunit, assessed by computational docking. GEV-induced cell death was caspase-independent, as investigated by a multiparametric approach, and culminates in severe morphological alterations in A549 cells, monitored by transmission electron microscopy, live cell imaging and flow cytometry. This non-canonical cell death was not preceded or accompanied by exacerbation of autophagy. In the presence of GEV, markers of autophagic flux (e.g. LC3I-II conversion) were impacted, even in presence of bafilomycin A1. Cell death induction remained unaffected by calpain, cathepsin, parthanatos or necroptosis inhibitors. Interestingly, GEV triggered caspase-dependent apoptosis in U937 acute myeloid leukemia cells, witnessing cancer-type specific cell death induction. Differential cell cycle modulation by this CG led to a G2/M arrest, cyclin B1 and p53 downregulation in A549, but not in U937 cells. We further extended the anti-cancer potential of GEV to 3D cell culture using clonogenic and spheroid formation assays and validated our findings in vivo by zebrafish xenografts. Altogether, GEV shows an interesting anticancer profile with the ability to exert cytotoxic effects via induction of different cell death modalities.

Keywords: lung cancer, cardiac glycoside, glucoevatromonoside, Apoptosis, non-canonical cell death

Received: 13 Sep 2017; Accepted: 19 Jan 2018.

Edited by:

Thomas Efferth, Johannes Gutenberg-Universität Mainz, Germany

Reviewed by:

Wentzel C. Gelderblom, Cape Peninsula University of Technology, South Africa
Linlin Lu, International Institute for Translational Chinese Medicine, China  

Copyright: © 2018 Schneider, Cerella, Lee, Mazumder, Kim, de Carvalho, Pádua, Munkert, Kreis, Kim, Christov, Kim, Dicato, Han, Braga, Simões and Diederich. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Marc Diederich, Seoul National University, Seoul, South Korea,