title: Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells.
abstract: 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.
authors: Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada.
authors: Alexander A
authors: AA
authors: Goldberg
authors: Adam
authors: A
authors: Beach
authors: Gerald F
authors: GF
authors: Davies
authors: Troy A A
authors: TA
authors: Harkness
authors: Andréa
authors: A
authors: Leblanc
authors: Vladimir I
authors: VI
authors: Titorenko
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053178:Caspase 6 / Q000378:metabolism; D002478:Cells, Cultured; D003902:Detergents / Q000494:pharmacology*; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting; D008095:Lithocholic Acid / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats
chemical_list: D003902:Detergents; C468783:H2AX protein, human; D006657:Histones; D008095:Lithocholic Acid; D006861:Hydrogen Peroxide; D053148:Caspase 3; D053178:Caspase 6