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.

Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances Cyclin D1 expression and promotes human endometrial cancer cell proliferation

“…Opposite biological effects by bile acids, such as induction of proliferation or apoptosis, have been reported by several authors in different experimental conditions. 13,14 To better understand this issue, we examined the effect of increasing doses of the primary bile acid chenodeoxicholyc (CDCA) on endometrial carcinoma cell growth by thymidine incorporation assay. As shown in Figure 1A, CDCA exerted divergent effects depending on its concentration.…”

Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells

“…Lithocholic acid (LCA) is a secondary bile acid produced by microflora in the gut, which we found to exhibit selective toxicity to human neuroblastoma cells and prostate cancer cells at relatively low concentrations that did not affect normal cells (Goldberg et al, 2011; Goldberg et al, 2013). LCA triggered both intrinsic and extrinsic pathways of apoptotic cell death that were, at least in part, caspase-dependent.…”

“…LCA triggered both intrinsic and extrinsic pathways of apoptotic cell death that were, at least in part, caspase-dependent. In addition, LCA selectively decreased the viability of human breast cancer and rat glioma cells (Goldberg et al, 2011). Various bile acids have been reported to have anti-neoplastic and anti-carcinogenic properties in a number of cancer cell models: chenodeoxycholic acid (CDCA) reduced growth of tamoxifen-resistant breast cancer cells by downregulation of human epidermal growth factor receptor 2 (HER2) promoter activity (Giordano et al, 2011), LCA and several of its synthetic enantiomers reduced colon cancer cell proliferation and viability (Katona et al, 2009).…”

Protoscolicidal effects of chenodeoxycholic acid on protoscoleces of Echinococcus granulosus

“…BAs are a group of water-soluble steroids formed after the catabolism of M A N U S C R I P T A C C E P T E D [31], prostate cancer [32], [33], and neuroblastoma [34]. Bile acids induced endoplasmic reticulum stress, which in turn stimulated apoptosis in HepG2 cells, in a hydrophobicity-dependent manner [35].…”