Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells
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1Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada
2Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
3Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada
4The Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada
Received: September 30, 2011; Accepted: October 11, 2011; Published: October 11, 2011;
Keywords: age-related diseases, cancer, neuroblastoma, breast cancer, glioma, anti-cancer drugs, apoptosis, bile acids, lithocholic acid
Vladimir I. Titorenko, email:
Andréa LeBlanc, email:
Aging is one of the major risk factors of cancer. The onset of cancer can be postponed by pharmacological and dietary anti-aging interventions. We recently found in yeast cellular models of aging that lithocholic acid (LCA) extends longevity. Here we show that, at concentrations that are not cytotoxic to primary cultures of human neurons, LCA kills the neuroblastoma (NB) cell lines BE(2)-m17, SK-n-SH, SK-n-MCIXC and Lan-1. In BE(2)-m17, SK-n-SH and SK-n-MCIXC cells, the LCA anti-tumor effect is due to apoptotic cell death. In contrast, the LCA-triggered death of Lan-1 cells is not caused by apoptosis. While low concentrations of LCA sensitize BE(2)-m17 and SK-n-MCIXC cells to hydrogen peroxide-induced apoptotic cell death controlled by mitochondria, these LCA concentrations make primary cultures of human neurons resistant to such a form of cell death. LCA kills BE(2)-m17 and SK-n-MCIXC cell lines by triggering not only the intrinsic (mitochondrial) apoptotic cell death pathway driven by mitochondrial outer membrane permeabilization and initiator caspase-9 activation, but also the extrinsic (death receptor) pathway of apoptosis involving activation of the initiator caspase-8. Based on these data, we propose a mechanism underlying a potent and selective anti-tumor effect of LCA in cultured human NB cells. Moreover, our finding that LCA kills cultured human breast cancer and rat glioma cells implies that it has a broad anti-tumor effect on cancer cells derived from different tissues and organisms.
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