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Cardiac Glycoside Glucoevatromonoside Induces Cancer Type-Specific Cell Death

Authors :
Naira F. Z. Schneider
Claudia Cerella
Jin-Young Lee
Aloran Mazumder
Kyung Rok Kim
Annelise de Carvalho
Jennifer Munkert
Rodrigo M. Pádua
Wolfgang Kreis
Kyu-Won Kim
Christo Christov
Mario Dicato
Hyun-Jung Kim
Byung Woo Han
Fernão C. Braga
Cláudia M. O. Simões
Marc Diederich
Source :
Frontiers in Pharmacology, Vol 9 (2018)
Publication Year :
2018
Publisher :
Frontiers Media S.A., 2018.

Abstract

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 toward non-cancerous cell types (lung MRC-5 and PBMC) and high-affinity binding to the Na+/K+-ATPase α 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.

Details

Language :
English
ISSN :
16639812
Volume :
9
Database :
Directory of Open Access Journals
Journal :
Frontiers in Pharmacology
Publication Type :
Academic Journal
Accession number :
edsdoj.1962657514af42deb6f0eab6afdc2661
Document Type :
article
Full Text :
https://doi.org/10.3389/fphar.2018.00070