Bile acids as endogenous etiologic agents in gastrointestinal cancer

Table 1 Bile acids induce DNA damage in cells of the esophagus

Cells/tissues	Bile acids that induce DNA damage	Assay for damage	Ref.
Cultured SV40-transformed, squamous esophageal epithelial cells (HET1-A) and Barrett’s associated adenocarcinoma cells (FLO-1)	DCA; also cocktail containing GCA, TCA, TCDCA	Comet assay1 for strand breaks	[18]
Cultured SV40-transformed, squamous esophageal epithelial cells (HET1-A)	DCA	Comet assay for strand breaks; evidence for oxidative mechanism involving nitric oxide	[19]
Cultured human adenocarcinoma cells (OE33)	DCA	Micronuclei assay; induction of micronuclei by DCA, reduced by antioxidants	[1520]
Biopsies from human Barrett’s esophageal metaplastic tissue	Cocktail containing DCA, GCA, TCA, GDCA, GCDCA	8-OHdG, an oxidized form of the DNA base guanine; assayed by IHC	[14]
Mouse model of esophagitis and Barrett’s esophagus	DCA (as dietary supplement; also zinc deficiency)	8-OHdG assayed by IHC	[17]

¹Comet assay, also known as the single cell gel electrophoresis assay; 8-OHdG: 8-hydroxydeoxyguanosine; IHC: Immunohistochemical assay.

Table 2 Bile acids induce apoptosis in liver cells

Cells/tissues	Bile acid(s) that induced apoptosis	Ref.
Isolated rat hepatocytes	GDCA	[6465]
	GCDCA	[5566]
	GCDCA, GCA	[57]
	GCDCA	[67]
Isolated rat and mouse hepatocytes	DCA	[68]
Liver tissue sections from rats fed DCA, and cultured human hepatocellular carcinoma cells (HuH-7)	DCA	[58]
Cultured rat hepatocyes (McNtcp.24 cells)	GCDC	[6970]
Cultured human hepatocellular carcinoma cells (HuH-7)	GCDCA	[71]
Rat hepatocytes and human hepatoma carcinoma cells (HuH-7)	Taurolithocholate-3-sulfate	[59]

Table 3 Bile acids induce ROS/RNS in colon cells

Cells/tissues	Bile acid(s) that induced ROS/RNS	Ref.
Human colon surgical resections	DCA (RNS)	[110]
Cultured human adenocarcinoma cells (CACO-2)	DCA, LCA (ROS)	[111]
Cultured human adenocarcinoma cells (HT-29)	DCA, LCA (ROS)	[112]
	DCA (ROS)	[36113]
	DCA (RNS)	[114]
Cultured human adenocarcinoma cells (HCT116)	DCA (ROS)	[109115116]
	DCA (RNS)	[117]
Rat colonic mucosa	DCA (ROS)	[118]
Mouse colonic mucosa	DCA (ROS, RNS)	[119]

Table 4 Bile acids induce DNA damage in colon cells

Cells/tissues	Bile acid(s)	Assay for DNA damage	Ref.
Isolated mouse colon crypt cells	LCA	Nucleoid sedimentation for strand breaks	[122]
Isolated human and rat colon cells LCA	LCA	Comet assay for strand breaks	[123]
Isolated rat colon cells	DCA	Immunostaining for poly (ADP-ribose) an indicator of DNA damage	[124]
Freshly isolated normal human colonocytes	DCA, CDCA	Comet assay for strand breaks	[125]
Cultured human adenocarcinoma cells (HT-29)	DCA, CDCA	Comet assay for strand breaks and modified comet assay for oxidative DNA damage
Cultured human adenocarcinoma cells (HT-29)	DCA, LCA	Comet assay for strand breaks	[112126]
Cultured human adenocarcinoma cells (CACO-2)	DCA, LCA	Comet assay for oxidative DNA damage	[111]
Cultured human colon adenocarcinoma cells (HCT-116 & HCT-15)	DCA	Comet assay for strand breaks	[127]
Cultured human colon adenocarcinoma cells (HCT-116 & HT-29)	DCA	Comet assay for strand breaks	[128]
Cultured human colon adenocarcinoma cells (HCT-116)	DCA	Induction of the DNA repair protein BRCA-1	[129]
		Induction of DNA damage inducible gene GADD153	[130]
		Comet assay	[116]
Cultured human colon adenocarcinoma cells (HCT-116 and HCT-15)	DCA	Induction of DNA damage inducible genes GADD34, GADD45, GADD153	[131]
Colon samples from mouse dietary colitis model	DCA	Oxidative DNA damage: 8-OHdG assayed by immunohistochemistry	[119]

Table 5 Bile acids induce apoptosis in colon cells

Cells/tissues	Bile acid(s) that induced apoptosis	Ref.
Biopsies from normal human colonic mucosa	DCA	[135–139]
Colon adenoma cell lines (AA/C1 and RG/C2), and carcinoma cell line (PC/JW/F1)	DCA	[140]
Cultured human adenocarcinoma cells (HT-29 and CaCo-2)	DCA	[141142]
Cultured human adenocarcinoma cells (HCT-116)	DCA, CDCA	[130143–146]
	DCA	[116147–149]
Cultured human adenocarcinoma cells (HT-29)	DCA	[114]
Cultured human adenocarcinoma cells (HT-29 and HCT-116)	DCA	[150]
	DCA	[128]
	DCA, LCA, CDCA	[151]
Cultured human adenocarcinoma cells (HT-29) and human fetal colonic mucosal cells (FHC)	DCA, LCA, CA, CDCA	[152]
Cultured human adenocarcinoma cells (HT-29, SW480, SW620)	DCA, CDCA	[153154]
Cultured human adenocarcinoma cells [HCT-116 (p53+) and HCT-15 (p53-)]	DCA	[127]
Cultured human adenocarcinoma cells (HCT-116SA apoptosis-sensitive and HCT-116RB, HCT-116RC and HCT-116RD apoptosis resistant)	DCA	[155]
Human colonic mucosal samples from surgical resections	DCA	[156]