Role of Induced Programmed Cell Death in the Chemopreventive Potential of Apigenin
Abstract
:1. Introduction
2. Apigenin
3. Physiological Functions of Apigenin
4. Apigenin in Cancer Therapy
5. Effect of Apigenin on Apoptosis
5.1. Apoptosis
5.2. Types of Apoptosis
5.2.1. Intrinsic (Mitochondrial) Pathway
5.2.2. Extrinsic (Death Receptor) Pathway
5.3. Induction of Apoptosis by Apigenin
5.3.1. Effect of Apigenin on Caspase-Mediated Apoptosis
5.3.2. Effect of Apigenin on Tumor Suppressor p53-Dependent Apoptosis
5.3.3. Effect of Apigenin on Tumor Suppressor p53-Independent Apoptosis
6. Effect of Apigenin on Autophagy
6.1. Autophagy
6.2. Types of Autophagy
6.3. Induction of Autophagy by Apigenin
Cancer/Cell Lines | Up-Regulation | Down-Regulation | Refs. |
---|---|---|---|
Breast | |||
T47D and MDA-MB-231 | LC3-I, LC3-II | [75] | |
Cevical | |||
HeLa | GRP78 | [169] | |
Colon | |||
HCT116 | LC3-II | Wnt, c-Myc, Axin2, cyclin D1, β-catenin, p-AKT, p70S6, p-p70, S6, 4EBP1, p-4EBP1 | [89,170] |
SW480 | LC3-II | Wnt | [170] |
HT-29 | Beclin-1, LC3-II | p62, p-mTOR, p-PI3K, p-AKT | [92] |
Gastric | |||
AGS and SNU-638 | Atg5, Beclin1, LC3-II AMPKα ULK1, GRP78, p-PERK, p-eIF2α ATF4, CHOP, GRP78, CD63 | p62, p-mTOR, Ezh2 | [168] |
Liver | |||
HepG2 and HepG2 xenograft | LC3-I, LC3-II, Atg5, Beclin1, LC3-II/I ratio, AMPK | SQSTM1/p62, p-PI3K, p-AKT, p-mTOR, p-mTOR/mTOR ratio, NQO2 | [111,171,172,173] |
Hep3B | LC3-II, Atg7, ROS | [115] | |
SMMC-7721 and SK-HEP-1 | LC3B-II, ULK1 | p62 | [174] |
Leukemia | |||
TF-1 | LC3-II, Atg5, Atg12, LMWPTP | p-Src, p-JAK2,p-STAT3, p-STAT5, p-SHP2, p-mTOR, p-p70S6K | [106] |
Lung | |||
H1975 | LC3-II | p-EGFR, Kras, c-Myc, HIF-1α, p-AMPKα | [175] |
Multiple myeloma | |||
NCI-H929 | Beclin1, LC3B-II | [176] | |
Neuroblastoma | |||
SH-SY5Y | LC3-II, p-AKT, mTOR | Beclin 1, TLR-4, Myd88 | [177] |
Pancreatic | |||
PANC-1 | LC3-I, LC3-II, p-AKT | p62, NRF2, SOD, CATALASE, HSP90, p-4EBP1 | [178] |
PaCa-44 | LC3-I, LC3-II, p62, NRF2, SOD, catalase, HSP90, 4EBP1, p-AKT | [178] | |
Renal | |||
ACHN and OS-RC-2 | Beclin1, LC3-II, p-AMPKα, p-JNK | Ki-67, PCNA, p62, p-PI3K, p-AKT, p-mTOR | [179] |
Skin | |||
COLO-16 and HEK | ATM, ATR, UPR, BiP, IRE1α, PERK, Atg, LC3-I, LC3-II | [180] | |
Thyroid | |||
BCPAP | Beclin1, LC3-I, LC3-II, Nrf2, HO-1 | p62 | [181] |
7. Effect of Apigenin on Necroptosis
7.1. Necroptosis
7.2. Necroptosis in Cancer
7.3. Induction of Necroptosis by Apigenin
8. Effect of Apigenin on Ferroptosis
8.1. Ferroptosis
8.2. Ferroptosis and Cancer
8.3. Induction of Ferroptosis by Apigenin
9. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cancer/Cell Lines | Up-Regulation | Down-Regulation | Refs. |
---|---|---|---|
Bladder | |||
T24 | PARP cleavage, caspase-3, -7 and -9 cleavage, Bax, Bak, Bad, p–p53, p53, p21, p27, Cyt c (cytosol) | p-Akt, PDK, PI3K, Bcl-2, Bcl-xL, cyclin A, B1, and E, CDK2, Cdc2, Cdc25c, Bcl-xL, Mcl-1, Cyt c (mitochondrial) | [68,69] |
RT112 | PARP cleavage | [70] | |
Breast | |||
SK-BR-3 | p53, p21, Bax, Cyt c, caspase-8 and -3, PARP, DFF45 cleavage, p27 | cyclin A, B, D, and E, CDK1, p-JAK, p-STAT3, VEGF, cyclin D1 and D3, CDK4 | [71,72,73] |
MDA-MB-231 and MDA-MB-231 xenograft | p-p53 (Ser-15), p21, Bax, PARP cleavage, IκBα, caspase-3 and -7, FOXO3a, p27, Cyt c | Bcl-xL, cyclin B1, Bcl-2, PI3K, PKB/AKT | [74,75,76,77] |
MCF-7 | p53, p-p53 (Ser-15), p21, caspase-8 and PARP cleavage, ROS, Cyt c, caspase-3, DFF45 cleavage, p27, FOXO3a | p-MDM2, p-JAK1, p-STAT3, NF-κB/p65, p-IκBα, cyclin D1 and D3, CDK4, PI3K, PKB/AKT | [72,77,78,79,80] |
BT-474 | caspase-8 and -3, PARP, Cyt c, DFF45 cleavage, p27 | p-JAK1, p-JAK2, p-STAT3, VEGF, HIF-1α, cyclin D1 and D3, CDK4 | [72,81] |
Hs578T | FOXO3a, p21, p27, PARP, Cyt c release | PI3K, PKB/AKT | [77] |
MDA-MB-453 | caspase-3, -6, -7, -8, and PARP cleavage, Cyt c release, DFF45 cleavage, p27 | procaspase-9, p-JAK2, p-STAT3 | [72,82,83] |
T47D | caspase-3 and PARP cleavage, Bax | Bcl-2, Bcl-xL | [75] |
HBL-100 | Cyt c, caspase-3, DFF45 cleavage, p27 | cyclin D1 and D3, CDK4 | [72] |
Cervical | |||
HeLa | p53, p21, caspase-2 and -3, Fas, mitochondrial redox impairment, PARP, ROS, AIF, Endo G, Cyt c | Bcl-2, MMP, superoxide dismutase | [84,85,86] |
SiHa, CaSki, and C-33A | mitochondrial redox impairment, ROS | MMP | [85] |
Colon | |||
HCT116 | p21, p53, NAG-1, Bim-EL, Bim-L, PARP cleavage | cyclin B1, Cdc2, Cdc25c, procaspase-3, -8, and -9, Mcl-1, Bcl-xL, STAT3, p-AKT, p-ERK | [87,88,89,90] |
LoVo | p21, NAG-1 | [88] | |
DLD-1 | PARP cleavage | Mcl-1, p-AKT, p-ERK, Bcl-xL, Mcl-1, STAT3 | [87,90] |
SW480 | Cdc2, cyclin B1 | [91] | |
HT-29 | Bax, PARP cleavage, caspase-3 and -8 | Cdc2, Bcl-2, m-TOR/PI3K/AKT, Bcl-xL, Mcl-1, STAT3, caspase-3 and -8, cyclin D1 | [90,91,92,93] |
Caco-2 | Cdc2 | [91] | |
COLO320 | PARP cleavage | Bcl-xL, Mcl-1, STAT3 | [90] |
Esophageal | |||
KYSE-510 | p21, PIG3, p63, p73, caspase-3 and -9, Bax | cyclin B1, Bcl-2 | [94] |
Eca-109 and KYSE-30 | PARP cleavage, caspase-8 | IL-6, VEGF | [95] |
Gastric | |||
HGC-27 and SGC-7901 | Bax, Bcl-2, caspase-3 | MMP | [96] |
Glioblastoma | |||
U-1242MG | PARP cleavage | MAPK, AKT, mTOR, Bcl-xL | [97] |
T98G and U-87MG | p-p38 MAPK, c-Jun1, caspase-3, -8, and -9, Bax, tBid, Smac (cytosol), SBDP, CAD (nuclear) | ROS, MMP, Bcl-2, Cyt c (mitochondrial), Smac (mitochondrial), calpastatin, ICAD | [98] |
Head and Neck | |||
SCC-25 | TRAIL, TRAIL-R1, and -R2, Fas, TNF-α, TNF-R1 and -R2, Bax, caspase-3 | Bcl-2 | [99] |
Melanoma | |||
A375 and C8161 | Cyt c release, Bax, Apaf-1, caspase-3, -9, and PARP cleavage | Bcl-2, Cyt c (mitochondrial), p-ERK1/2, p-AKT, p-mTOR | [50,100,101] |
Leukemia | |||
THP-1 | caspase-3 activity, p-p38, p-ERK, PKCδ activity, p-ATM | caspase-9 activity, p-H2AX | [102,103] |
U937 | caspase-3, -7, -9, and PARP cleavage, p-JNK, Bcl-2 cleavage | hTERT, c-Myc, Mcl-1, p-AKT, AKT, p-Bad, p-mTOR, p-GSK3β, JNK, Mcl-1, Bcl-2 | [104,105] |
HL60 | p-Cdc2, p-p38, caspase-3, -8, and PARP cleavage | PI3Kp85, p-AKT, p-GSK3β, p-JAK2, p-Src, p-STAT3 | [106,107] |
TF-1 | LMWPTP | CDK6, p-Src, p-JAK2, p-SHP2, p-STAT3 and 5, p-p70S6K | [106] |
Liver | |||
Huh-7 | caspase-3, -8, and -9 cleavage, PARP, Bax/Bcl-2 ratio | [108,109] | |
HepG2 | caspase-3, -7, -8, -9, and -10, Bid, p21, p16, PARP cleavage, Bax, DR5, ROS, TNF-α, IFN-γ | Bcl-2, PI3K/AKT/mTOR, p-LRP6, Skp2 | [48,110,111,112,113,114] |
Hep3B | DR5, ROS, caspase activation | [115] | |
SK-HEP-1 | ROS, caspase 3, PARP | MMP, Bcl-2 | [116] |
BEL-7402 and BEL-7402 xenograft | ROS, caspase 3, PARP | MMP, Bcl-2, Nrf2 | [116,117] |
Lung | |||
A549 | p21, Cyt c release, Bax, p53, p-p53, Wee1, Chk2, Bid, GRP78, caspase-3, -9, and PARP cleavage, GADD153, AIF, MAPK, DR4, DR5 | XIAP, Bcl-2, MMP, cyclin B, Cdc25c, procaspase-8, Bcl-xL, NF-κB, ERK, AKT, Cyt c (mitochondrial) | [81,100,118,119,120] |
H460 | p21, Bax, FasL, p53, AIF, Cyt c, caspase-3, GRP78, GADD153 | XIAP, Bcl-2, Bid, procaspase-8 | [118,121,122] |
H1299 | MAPK, DR4, DR5, Bax, Bad | Bcl-xL, Bcl-2, NF-κB, ERK, AKT | [120] |
Diffuse large B-cell lymphoma | |||
U2932 and OCI-LY10 | caspase family, PARP cleavage | Bcl-xL, PI3K/mTOR, p-GS3K-β, MCL-X, p38, p-p65, p-AKT | [123] |
Mesothelioma | |||
MM-B1, H-Meso-1 and MM-F1 | Bax/Bcl-2 ratio, p53, caspase-8, -9, and PARP-1 cleavage | p-ERK1/2, p-JNK, p-p38 MAPK, p-AKT, c-Jun, p-c-Jun, NF-κB nuclear translocation | [124] |
Multiple myeloma | |||
U266 and RPMI 8226 | PARP cleavage | p-STAT3, p-ERK, p-AKT, NF-κB, Mcl-1, Bcl-2, Bcl-xL, XIAP, survivin | [125] |
Neuroblastoma | |||
SK-N-DZ, SK-N-BE2, SK-N-DZ and SK-N-BE2 xenograft | caspase-3, -8, and PARP cleavage, Bax, Bid, tBid, calpain, ICAD fragment, p21, Noxa, PUMA, p53, ICAD, SBDP | N-Myc, E-cadherin, Notch-1, hTERT, PCNA, Smac, survivin, SBDP, Bcl-2, Mcl-1 | [126,127,128,129] |
NUB-7 | PARP cleavage, p53 (NE), p21, Bax, p-ERK | [130] | |
IMR-32 | Bax, Noxa, PUMA, p53, caspase-3, ICAD | Bcl-2, Mcl-1 | [128] |
Oral | |||
SCC-25 | TRAIL, TRAIL-R1 and -R2, Fas, TNF-α, TNF-R1 and -R2, Bax, caspase-3 | cyclin D1 and E, CDK1 | [99] |
Osteosarcoma | |||
U-2 OS | Bax, PARP cleavage, p53, AIF | procaspase-3, -8, and -9, GADD153 (NE) | [131] |
Ovarian | |||
SKOV-3 | caspase-3 and -9, Bax, Bcl-2, COX-2, ROS | [132,133,134] | |
A2780 and OVCAR-3 | ROS, MDA, caspase-3 and -9 | [133] | |
Pancreatic | |||
BxPC-3 | Ac-p53, p21, PUMA, Cyt c release, caspase-3 cleavage | Bcl-xL/p53 interaction, Bcl-xL/PUMA interaction, cyclin B1, Bcl-2, XIAP, p-GSK3β, NF-κB/p65 (NE) | [135,136,137] |
MIA PaCa-2 | Ac-p53, p21, PUMA, Cyt c release, PARP cleavage | Bcl-xL/p53 interaction, Bcl-xL/PUMA interaction | [135,138] |
PANC-1 | Cyt c release, caspase-3 cleavage | cyclin B1, XIAP, p-GSK3β, NF-κB/p65 (NE) | [136] |
PEL | |||
BC3, BCBL1, and B | p53 | STAT3, ROS | [139] |
Prostate | |||
22Rv1 and 22Rv1 xenograft | p53, p-p53, p21, p14, Cyt c release, Bax, Apaf-1, caspase-3, -8, -9, and PARP cleavage | MDM2, MMP, Bcl-2, Bcl-xL, p-IKKα, NF-ĸB/p65, PCNA, HDAC1 and 3, Bcl-2 | [140,141,142] |
PC-3 and PC-3 xenograft | caspase-3, -9, and PARP cleavage, Bax, Bad, Ku70, Cyt c release, p27, p21 | XIAP, cIAP-1, -2, Bcl-2, Bcl-xL, survivin, HDAC1, procaspase-3, -7, and -9, cyclin D1, p-IKKα, NF-ĸB/p65, PCNA, ER-β, PSMA5, PLK-1, HDAC1, and 3, Bcl-2 | [141,142,143,144,145,146,147] |
LNCaP | p21, p27, Bax, PARP cleavage, Cyt c release | cyclin D1, D2, and E, CDK2, 4, and 6, Bcl-2, procaspase-3, -8, and -9, NF-κB/p65, PLK-1 | [51,145,147] |
DU145 | caspase-3, -9, and PARP cleavage, DR5, Cyt c release | XIAP, cIAP-1 and -2, survivin, procaspase-3, -7, and -9 | [143,145,148] |
Renal | |||
ACHN, 786-O, and Caki-1 | p53, Bax, caspase-3 and -9 | [149] | |
Thyroid | |||
FRO | c-Myc, Bid, Fas, p-p53, caspase-3 and PARP cleavage | Bcl-2, p27, p21 | [150] |
Cancer/Cell Lines | Up-Regulation | Down-Regulation | Refs. |
---|---|---|---|
Mesothelioma | |||
MSTO-211H and H2452 | ROS, γ-H2AX, p-ATM, p-ATR, p-CHK1, p-CHK2, Bax, caspase-3 and PARP cleavage, p-MLKL, p-RIP3, Bax/Bcl-2 ratio | MMP, ATP, Bcl-2 | [193] |
Pancreatic | |||
AsPC-1 | p-ATM, γ-H2AX, p-p53, Bim, Bid, Bax, PARP cleavage, caspasae-3, -8, and -9, Cyt c, AIF1, p62, LC3B, p-MLKL, p-RIP | Bcl-2 | [194] |
Cancer/Cell Lines | Up-Regulation | Down-Regulation | Refs. |
---|---|---|---|
Lung | |||
A549 | ROS, COX-2, p53, MDA, Bax, caspase-3 and -8, Cyt c | GPX4, FTH1, SOD, Bcl-2 | [207] |
Multiple Myeloma | |||
HEK293 | caspase-3 and -9, p38, JNK, LC3-II, Beclin-1, ROS | AKT, MMP, STAT1, COX-2, iNOS | [176] |
NCI-H929 | LC3-II, Beclin-1, ROS | MMP | [208] |
Neuroblastoma | |||
SH-SY5Y | GPX4 | MMP | [206] |
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Jang, J.Y.; Sung, B.; Kim, N.D. Role of Induced Programmed Cell Death in the Chemopreventive Potential of Apigenin. Int. J. Mol. Sci. 2022, 23, 3757. https://doi.org/10.3390/ijms23073757
Jang JY, Sung B, Kim ND. Role of Induced Programmed Cell Death in the Chemopreventive Potential of Apigenin. International Journal of Molecular Sciences. 2022; 23(7):3757. https://doi.org/10.3390/ijms23073757
Chicago/Turabian StyleJang, Jung Yoon, Bokyung Sung, and Nam Deuk Kim. 2022. "Role of Induced Programmed Cell Death in the Chemopreventive Potential of Apigenin" International Journal of Molecular Sciences 23, no. 7: 3757. https://doi.org/10.3390/ijms23073757