Selective ROS-dependent p53-associated anticancer effects of the hypoxoside derivative rooperol on human teratocarcinomal cancer stem-like cells
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Cancer stem cells (CSCs) are potential targets for innovative anticancer therapies that involve natural products with potential chemopreventive effects. We therefore analyzed the antineoplastic activity of rooperol, the aglycone of the plant-derived compound hypoxoside, on a model of Oct4-expressing cancer stem-like cell, i.e. the human embryonal carcinoma (EC) cell NT2/D1.
Rooperol selectively inhibited the proliferation of NT2/D1 cells in a concentration-dependent manner and had no effect on either normal embryonic fibroblasts which are more restrictive pluripotent stem cells or on NCCIT p53-mutant EC cells. Accordingly, rooperol only eliminates colon carcinoma cells expressing p53.
Rooperol treatment triggered cell death on NT2/D1 cells through the alteration of mitochondrial membrane potential and production of reactive oxygen species (ROS). Rooperol-induced apoptosis was associated with activation of p53 and concentration-dependent changes of the expression levels of both caspase 3 and poly ADP ribose polymerase type 1 cleaved subunits. These modifications were accompanied by a downregulation of Oct4 and its two partners involved in the maintenance of cell pluripotency and self-renewal, Nanog and Sox2.
Treatment with intracellular membrane permeant O2 − scavengers prevented rooperol-induced apoptosis and upregulation of the expression of p53 and active caspase-3. Our findings indicate that rooperol mediates its growth inhibitory effects on CSCs via a mitochondrial redox-sensitive mechanism. We propose that abrogating the expression of the stemness regulators is a prerequisite for rooperol to fully exert its pro-apoptotic properties on wild-type p53-bearing CSCs.
KeywordsCancer stem-like cells Rooperol Apoptosis Reactive oxygen species p53 Oct4
This work is dedicated to the memory of Dr. A.C. Allison. This study has been supported by grants from the CCIR-GE of the “Ligue contre le Cancer” (Comité du Grand Est, France). Fathi Emhemmed is supported by a fellowship from the Higher Education Commission of Libya.
Conflict of interest
The authors declare no conflict of interest.
- 2.Sharif T, Emhemmed F, Fuhrmann G (2011) Towards new anticancer strategies by targeting cancer stem cells with phytochemical compounds. In: Shostak S (ed) Cancer Stem Cells - The Cutting Edge. Rijeka, Croatia, Intech, pp 431–456Google Scholar
- 9.Sharif T, Stambouli M, Burrus B, Emhemmed F, Dandache I, Auger C, Etienne-Selloum N, Schini-Kerth VB, Fuhrmann G (2013) The polyphenolic-rich Aronia melanocarpa juice kills teratocarcinomal cancer stem-like cells, but not their differentiated counterparts. J Funct Foods 5:1244–1252CrossRefGoogle Scholar
- 10.Emhemmed F, Ali Azouaou S, Thuaud F, Schini-Kerth V, Désaubry L, Muller CD, Fuhrmann G (2014) Selective anticancer effects of a synthetic flavagline on human Oct4-expressing cancer stem-like cells via a p38 MAPK-dependent caspase-3-dependent pathway. Biochem Pharmacol 89:185–196PubMedCrossRefGoogle Scholar
- 20.Sharif T, Alhosin M, Auger C, Minker C, Kim JH, Etienne-Selloum N, Bories P, Gronemeyer H, Lobstein A, Bronner C, Fuhrmann G, Schini-Kerth VB (2012) Aronia melanocarpa juice induces a redox-sensitive p73-related caspase 3-dependent apoptosis in human leukemia cells. PLoS One 7:e32526PubMedCentralPubMedCrossRefGoogle Scholar
- 22.Sharif T, Auger C, Alhosin M, Ebel C, Achour M, Etienne-Selloum N, Fuhrmann G, Bronner C, Schini-Kerth VB (2010) Red wine polyphenols cause growth inhibition and apoptosis in acute lymphoblastic leukaemia cells by inducing a redox-sensitive up-regulation of p73 and down-regulation of UHRF1. Eur J Cancer 46:983–994PubMedCrossRefGoogle Scholar