Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review
Abstract
:1. Introduction
2. Role of Natural Bile Acids in Cancer
3. Effect of Natural Bile Acids on Apoptosis
3.1. Apoptosis
3.2. Types of Apoptosis
3.3. Bile Acid-Related Apoptosis
3.3.1. Effects of Primary Bile Acids on Apoptosis
3.3.2. Effects of Secondary and Tertiary Bile Acids on Apoptosis
4. Effect of Natural Bile Acids on Autophagy
4.1. Autophagy
4.2. Types of Autophagy
4.3. Bile Acid-Related Autophagy
5. Effect of Natural Bile Acids on Necroptosis
5.1. Necroptosis
5.2. Necroptosis in Cancer
5.3. Bile Acid-Related Necroptosis
6. Cell Death Mechanism of Synthetic Bile Acid Derivatives in Cancer
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Types | Target Molecules | Model(s) | Refs. | |
---|---|---|---|---|
Up-Regulation | Down-Regulation | |||
CDCA | mitochondrial transition permeability, ROS, caspase-3 and -9, cleavage of Bcl-2, Bax | ΔΨm | Colon cancer cells (BCS-TC2) | [69] |
cleavage of PARP, mitochondrial depolarization, Cyt c (cytosolic) | Hepatocellular carcinoma cells (HepG2) | [70] | ||
E-cadherin, p53, p21, Bax, GADD45, P2xm, Mcl-1 | N-cadherin, Snail, integrin α5, integrin β1, p-FAK, IGFBP3, Bcl-2 | Lung cancer cells (A549, H1650), xenograft (A549) | [71] | |
GCDCA | Cyt c, DR5, TNF-R1, cleaved caspase-3, -7, -8, and BAP31, AP-1, p-JNK, p-p38, Bax, Bip, CHOP, LDH | DR6 | Hepatocellular carcinoma cells (HepG2, HepG2-Ntcp, HuH-BAT) | [72,73,74] |
DCA | NF-κB (nuclear), caspase-3, -6, and -9, cleavage of PARP and PKC ε, PKC β1, ratio of Bax to Bcl-2, p53, cyclin D1 | Bcl-2, cyclin D1, Cdk2, ΔΨm | Gastric cancer cells (AGS, BGC-823, SGC-7901) | [41,75,76] |
p-ERK, p-p38, p-Elk-1, p-ATF2, Cyt c release, caspase-3, -8, and -9, cleavage of PARP, ROS, p-p38, p-ERK1/2, cleavage of Bcl-2, Bax | c-Myc, ΔΨm, Bid | Colon cancer cells (HCT-116, BCS-TC2, HT-29) | [69,77,78,79,80,81] | |
LCA | p53 | Bcl-2, p-Akt, SREBP-1c, FASN, ACACA, ERα | Breast cancer cells (MCF-7, MDA-MB-231) | [82] |
caspase-3, -8, and -9 activity, cleavage of PARP, Bid, Bax | Bcl-2, ΔΨm | Prostate cancer cells (PC-3, LNCaP) | [83] | |
TGR5, caspase-3, -6, -7, -8, and-9 activity | Neuroblastoma cells (WT-CLS1, SK-NEP1, BE(2)-m17, SK-n-SH, SK-n-MCIXC, Lan-1) | [84,85] | ||
ROS | ΔΨm | Hepatocellular carcinoma cells (HepG2) | [86] | |
UDCA | ROS, cleaved caspase-3, -9, and PARP-1, Bax/Bcl-2 ratio, Apaf-1, p21, p53, Cyt c | ΔΨm, Cdk1, cyclin B1, Bcl-2, MMP-2 and -9, | Melanoma cells (M14 and A375) | [49] |
ROS, Bip, IRE1α, ATF4, ATF6, p-PERK, CHOP, p21, p53, p-ERK | ΔΨm, Cdk2, Cdk4, Cdk6, pRb, cyclin D1, RIP3, Bcl-2 | Glioblastoma multiforme cells (A172, LN229) | [87] | |
TRAIL, DR4, DR5, Bax, Cyt c, cleavage of PARP | Bcl-xL, pro-caspase-3 and -8 | Prostate cancer cells (DU145) | [88] | |
Bax, Samc, caspase-2, -3, -8, and -9, Apaf-1 | Bcl-2, Livin | Hepatocellular carcinoma cells (HepG2) | [89,90] | |
Bax, Apaf-1, cleavage of caspase-3 and -9, Cyt c (cytosolic) | Bcl-2, Cyt c (mitochondrial) | Hepatocellular carcinoma xenografts (BEL7402) | [18] | |
p-ERK1/2, p-MEK1/2, caspase-3, -6, and -8, cleavage of PARP, DR5, TRAIL, ROS, PKCδ | Gastric cancer cells (SNU601, SNU638) | [91,92] | ||
DR5 | Gastric cancer cell xenografts (SNU601) | [92] | ||
Bax, caspase-3, Cyt c, PARP | Bcl-2, TGF-β, VEGF, N-cadherin, SIRT-1, p-Akt, p-mTOR | Anaplastic thyroid cancer (FRO) | [93] | |
caspase-3, -8, and -9, Bax, Fas, FasL, TRAIL, DR4, DR5, IκB-α | Bcl-2, Bcl-xL, XIAP, cIAP-1, cIAP-2, survival, NF-κB | Oral squamous carcinoma cells (HSC-3) | [20] |
Types | Target Molecules | Model (s) | Refs. | |
---|---|---|---|---|
Up-Regulation | Down-Regulation | |||
DCA | Beclin-1 | Esophageal adenocarcinoma (CP-A) | [109] | |
LCA | p-JNK, p-eIF2α, CHOP, ROS, caspase-3, LC3BⅡ, ATG5 | BIM, PUMA, | Prostate cancer cells (PC-3, DU-145) | [110] |
UDCA | Cleaved caspase-3, Cyt c, cleavage of PARP, LC3Ⅱ, caspase-3, -6, and -8, DR5, c-FLIP(L) | ATG5 | Gastric cancer subline (SNU601/WT, SNU601/R) | [111] |
Types | Target Molecules | Model (s) | Refs. | |
---|---|---|---|---|
Up-Regulation | Down-Regulation | |||
CA | RIPK3, p-RIPK3, IL-8, p-JNK | Hepatocellular carcinoma cells (HepG2) | [152] | |
TCA | FXR | ATG7 | Rat pancreatic acinar-like cancer cell line (AR42J) | [159] |
FXR, SQSTM1/p62, FOXO3 (cytosolic), MLKL, caspase-3, -8, and -9, Bax, RIPK3, p-MLKL | ATG5, ATG7, LC3 (LC3-II), Beclin-1 | Chronic pancreatitis tissue | [159] | |
UDCA | RIPK3, p-RIPK3, p-JNK | Hepatocellular carcinoma cells (HepG2) | [152] | |
CDCA | p-RIPK3, IL-8 | Hepatocellular carcinoma cells (HepG2) | [152] | |
GCDCA | MLKL, p-MLKL, RIPK3 | Liver of patients with PBC | [155] | |
MLKL, p-MLKL, RIPK1, RIPK3 | Liver of mice after BDL | [155] | ||
FXR | ATG5, ATG7 | Pancreatic cancer cell lines (MIA PaCa-2, BxPC-3) | [159] | |
FXR | ATG5, ATG7 | Rat pancreatic acinar-like cancer cell line (AR42J) | [159] | |
FXR, SQSTM1/p62, FOXO3 (cytosolic), MLKL, caspase-3, -8, and -9, Bax, RIPK3, p-MLKL | ATG5, ATG7, LC3 (LC3-II), Beclin-1 | Chronic pancreatitis tissue | [159] | |
TCDCA | RIPK3, p-RIPK3, | Hepatocellular carcinoma cells (HepG2) | [152] | |
LCA GLCA TLCA | RIPK3, p-RIPK3 | Hepatocellular carcinoma cells (HepG2) | [152] |
Derivatives | Types | Mechanism | Target Molecules | Model (s) | Refs. | |
---|---|---|---|---|---|---|
Up-Regulation | Down-Regulation | |||||
HS-1030 | UDCA derivative | apoptosis | p21 | cyclin E, Cdk2, Cdk4, Cdk6, E2F-1 | Colon cancer cells (HT-29) | [22] |
HS-1183 | UDCA derivative | apoptosis | cleavage of PARP | pro-caspase-3 and -8 | Leukemic T cells (Jurkat cells) | [161] |
apoptosis | p21 | cyclin D1, Cdk4, Cdk6, E2F-1 | Colon cancer cells (HT-29) | [22] | ||
apoptosis | cleavage of PARP, Bax, c-Jun, p-JNK, AP-1 | p-p38, p50, p65, IkB-α | Cervical carcinoma cells (SiHa) | [162] | ||
apoptosis | Bax, cleavages of lamin B and PARP, p21, p53 | Bcl-2, cyclin D3, pRb | Breast cancer cells (MCF-7, MDA-MB-231) | [163] | ||
apoptosis | p21 | pRb | Prostate cancer cells (PC-3) | [164] | ||
HS-1199 | CDCA derivative | apoptosis | cleavage of PARP | pro-caspase-3 and -8 | Leukemic T cells (Jurkat cells) | [161] |
apoptosis | p21 | cyclin D1, cyclin E, Cdk2, Cdk4, Cdk6, E2F-1 | Colon cancer cells (HT-29) | [22] | ||
apoptosis | cleavage of PARP, Bax, c-Jun, p-JNK, AP-1 | p-p38, p-ERK | Cervical carcinoma cells (SiHa) | [162] | ||
apoptosis | Bax, cleavages of lamin B and PARP, p21, p53 | Bcl-2, cyclin D1, cyclin D3, pRb | Breast cancer cells (MCF-7, MDA-MB-231) | [163] | ||
apoptosis | cleavage of PARP, p21 | pRb, cyclin D1, cyclin D3 | Prostate cancer cells (PC-3) | [164] | ||
apoptosis | Cyt c, cleavage of PARP and DFF45, AIF(N), Nur77 | ΔΨm, pro-caspase-3, XIAP | Stomach cancer cells (SNU-1) | [165,166] | ||
apoptosis | cleavage of PARP, Cyt c | pro-caspase-3, ΔΨm | Malignant glioblastoma cells (U-118MG, U-87MG, T98G, U-373MG) | [167] | ||
HS-1200 | CDCA derivative | apoptosis | cleavage of PARP | pro-caspase-3 and -8 | Leukemic T cells (Jurkat cells) | [161] |
apoptosis | cleavage of PARP, p21 | cyclin D1, cyclin E, Cdk2, Cdk4, Cdk6, pRb, E2F-1 | Colon cancer cells (HT-29) | [22] | ||
apoptosis | cleavage of PARP, Bax, c-Jun, p-JNK, AP-1 | p-p38, p-ERK, p65(total), p50(total), IkB-α(total) | Cervical carcinoma cells (SiHa) | [162] | ||
apoptosis | Bax, cleavages of lamin B and PARP, p21, p53, AIF | Bcl-2, cyclin D1, cyclin D3, pRb | Breast cancer cells (MCF-7, MDA-MB-231) | [163,168] | ||
apoptosis | cleavage of PARP, p21 | pRb, Cdk2, cyclin D1, cyclin D3 | Prostate cancer cells (PC-3) | [164] | ||
apoptosis | Cyt c, cleavage of PARP and DFF45, AIF(N), Nur77 | ΔΨm, pro-caspase-3, XIAP | Stomach cancer cells (SNU-1) | [165,166] | ||
apoptosis | cleavage of PARP, Cyt c | pro-caspase-3, ΔΨm | Malignant glioblastoma cells (U-118MG, U-87MG, T98G, U-373MG), Xenografts (U87MG) | [167] | ||
apoptosis | Bax, p53, p21, p27, Egr-1, caspase-3 and 9, cleavage of PARP, Cyt c (cytosolic) | Bcl-2, cyclin D1, Cdk2, cyclin A, E2F-1, Mdm2, COX-2, Cyt c (mitochondrial), ΔΨm | Hepatoma cells (HepG2, Hep3B, BEL7402) | [169,170] | ||
apoptosis | AIF, CAD, cleavage of PARP | ΔΨm, pro-caspase-3 and -7, PARP | Thyroid carcinoma (KAT 18) | [171] | ||
ent-CDCA | enantiomers of CDCA | apoptosis | pro-caspase-3 and -9 | Colon cancer cells (HT-29, HCT-116) | [23] | |
ent-DCA | enantiomers of DCA | apoptosis | pro-caspase-3 and -9 | Colon cancer cells (HT-29, HCT-116) | [23] | |
ent-LCA | enantiomers of LCA | apoptosis | CD95, ROS, | pro-caspase-2, -3, -8, and -9, Bid | Colon cancer cells (HT-29, HCT-116) | [23] |
6af and 6cf | bile-acid-appended triazolyl aryl ketones | apoptosis | Breast cancer cells (MCF-7) | [24] | ||
CDC-PTX UDC-PTX | CDCA derivative UDCA derivative | apoptosis | Acute promyelocytic leukemia cells (HL60, NB4) | [25] | ||
CDCA derivative UDCA derivative | apoptosis | Colon cancer cells (RKO, HCT-116) | [25] | |||
7b | Piperazinyl bile acid derivative | apoptosis | Multiple myeloma (KMS-11), Colonic cancer cells (HCT-116) | [26] | ||
LCA-TMA1, CDCA-TMA2, DCA-TMA2, and CA-TMA3 | cationic bile acid based facial amphiphiles featuring trimethyl ammonium head groups | apoptosis | Colon cancer cells (HCT-116, DLD-1) | [27] | ||
compound IIIb | CDCA-substituted piperazine conjugate | apoptosis | cleavage of Mcl-1 and PARP-1, Ip-IκBα, DNA fragmentation | IκBα | Multiple myeloma (KMS-11) | [28] |
LCA-PIP1 | LCA amphiphile | apoptosis | pro-caspase-3, -7, and -8 | Colon cancer cells (HCT-116) Xenograft (HCT-116) | [29] | |
CA-Tam3-Am | CA−tamoxifen conjugate | apoptosis | Bax, Bid, Bad, caspase-9, cleaved caspase-3 and -8, Cyt c, ROS | Bcl-2, Bcl-xL, survivin | Breast cancer cells (MCF-7, T47D, MDA-MB 231) | [30] |
norUDCA | UDCA derivative | autophagy | ratio of LC3-II to LC3-I, ATG5, ATG5/ATG12, p-AMPK, p-ULK1(Ser317), p-ULK1(Ser555), p-ULK1(Ser777) | p62, α1ATZ, p-mTOR, p-ULK1(Ser757) | Cervical cancer cells (HTOZ) | [31] |
compound 9 | DCA derivative | apoptosis, autophagy | caspase-3 and -7, ROS | Duodenal carcinoma cells (HuTu 80) | [32] |
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Jang, J.Y.; Im, E.; Choi, Y.H.; Kim, N.D. Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review. Int. J. Mol. Sci. 2022, 23, 7184. https://doi.org/10.3390/ijms23137184
Jang JY, Im E, Choi YH, Kim ND. Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review. International Journal of Molecular Sciences. 2022; 23(13):7184. https://doi.org/10.3390/ijms23137184
Chicago/Turabian StyleJang, Jung Yoon, Eunok Im, Yung Hyun Choi, and Nam Deuk Kim. 2022. "Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review" International Journal of Molecular Sciences 23, no. 13: 7184. https://doi.org/10.3390/ijms23137184