Table 1.
Effects of green tea catechins in apoptosis and cell growth.
| Model | Compound/Component | Effect | Reference |
|---|---|---|---|
| In vitro | |||
| MOLT 4B | C, EC, ECG, EGC and EGCG 0.025–0.100 mM (3 days) |
Inhibited the growth and apoptosis detected by DNA fragmentation and morphological change and inhibited the ornithine decarboxylase (ODC) activity (↓) | [36] |
| Leukemia blast cells from AML patients HEL |
EGCG 0–100 nM (8–72 h) |
Inhibited proliferation and the effects of TNFα or TPA (↓) and down modulated c-Kit (↓) | [15] |
| HL60 | Tea polyphenols 60–4000 µg/mL (5–48 h) |
Induced apoptosis detected by internucleosomal DNA degradation, DNA ladder and apoptotic vehicles | [34] |
| U937 | EGCG 100–400 µM (16 h) |
Induced apoptosis detected by formation of DNA ladder, chromatin condensation and apoptotic bodies | [48] |
| U937 | EGCG 100–400 µM (6–16 h) |
Induced apoptosis (DNA fragmentation) | [49] |
| U937 JURKAT |
EGCG IC50 = 26.0 µM (12 h) IC50 = 25.3 µM (12 h) |
Inhibited cell growth (↓ ATP content), induction of apoptosis (morphological changes, chromosome condensation and DNA fragmentation ladder) | [46] |
| Peripheral blood T-lymphocytes of acute T-cell leukemia patient KODV |
Tea (green tea polyphenols) EGCG 3-27 µg/mL (3 days) |
Inhibited cell growth, induction of apoptosis (DNA fragmentation) and suppression of HTLV-1 pX mRNA | [44] |
| HL60 JURKAT K562 |
EGC 50 µg/mL (2–24 h) |
Induced apoptosis (DNA fragmentation and PARP cleavage) | [30] |
| U937 | EGCG 200 and 400 µM (0–16 h) |
Induced apoptosis (formation of apoptotic bodies, DNA ladder formation, ↑ caspase 8 activity and interaction with Fas) | [23] |
| U937 | EGCG and GHF (high molecular weight fraction from green tea) EGCG—200 µM IC50 = 49 µM GHF 1.2 mg/mL IC50 = 0.61 mg/mL (20 h) |
Induced apoptosis (formation of apoptotic bodies and DNA ladder formation) | [22] |
| HL60 | EGCG | Induced apoptosis (internucleosomal DNA fragmentation) and decreased activities of MnSOD and CuZnSOD | [32] |
| L1210 | EGCG 200 µM (24 h) |
Induced apoptosis (DNA ladder) | [52] |
| NALM6 Health human lymphocytes |
EGCG 10–100 µM (24 h) |
Reduced viability by DNA damage and PAR formation (poly (APD-ribosyl) (↑)) | [37] |
| K562 V-79 | EGCG 50–500 µM (1–48 h) |
Inhibited cell growth (↓ thymidine incorporation) and induction of apoptosis (chromatin condensation, nuclear and DNA fragmentation and ↑ caspase 3 and 8 activity) Protection of normal cells from genotoxic or carcinogenic assault |
[47] |
| WEHI-3B JCS | EGCG 0–40 µM (48 h) IC50 = 16.8–31.0 µM |
Inhibited proliferation (↓ thymidine incorporation), the ability to form colonies and induce apoptosis (formation of DNA ladder, condensed and fragmented nuclear structure) | [50] |
| JURKAT | EGCG and synthetic analogs of EGCG (with modification in the A-ring, C-ring or ester bond) 0–2.5 µM (0–24 h) |
Induced apoptosis by inhibiting proteasomal activity (DNA fragmentation) Induced cycle arrest (↑ G1 population, ↑ sub-G1 DNA cell population) |
[56] |
| JURKAT NIH/3T3 |
EGCG and green tea extract 0–50 µM (0–48 h) |
Induced apoptosis by inhibiting proteasomal chymotrypsin-like activity (↑ ubiquitinated proteins, PARP cleavage and caspase-3/-7 activation) | [38] |
| Primary chronic lymphocytic leukemia B-cells Human splenic B-cells |
EGCG 0–40 µg/mL (24 h) |
Induced apoptosis (caspase 3 activation, PARP cleavage); suppression of Bcl-2, XIAP and Mcl-1 (↓) and VEGF-R1 and VEGF-R2 phosphorylation (↓) | [43] |
| Primary chronic lymphocytic leukemia B-cells Human splenic B-cells |
EGCG 3.12–25 µg/mL (24 h) |
Induced apoptosis, inhibition of VEGF receptor activation, ↓ levels of serine p-STAT3 and ↓ Mcl-1 and XIAP | [42] |
| HL60 K652 | Green tea (GT)/EGCG 0–1000 µg/mL (24 h) IC50 HL60 GT = 375/EGCG = 60 K562 GT = 400/EGCG = 58 |
Induced apoptosis (chromatin condensation, nuclear fragmentation, apoptotic bodies, cell shrinkage and ↓ thymidine incorporation in nuclear DNA) | [25] |
| HL60 K562 |
EGCG 0–100 µg/mL (24 h) |
Induced apoptosis (chromatin condensation, nuclear fragmentation, DNA fragmentation, caspase-3/-8 activation, ↓ Bcl-2 ↑ Bax) | [35] |
| UF-1 NB4 Fresh cells from patients with AML |
EGCG 100 µM (0–24 h) IC50 = 50 µM |
ROS production, induced apoptosis: mitochondrial dysfunction; release of cytocromo C; Bax ↑, Blc-2 and survivin ↓; caspase-3 ↑; PARP cleavage; DNA ladder. Induced cycle arrest—↑ G1 phase and ↓ S phase; ↑ expression of p21 and p27 |
[26] |
| IM9, RPMI8226 and U266 HS-sultan Bone marrow samples from multiple myeloma |
EC, ECG, EGC and EGCG 0–100 µmol/L (0–72 h) IC50 (EGCG) HS-sultan 17 µmol/L IM9 20 µmol/L |
Induced apoptosis through ROS production (↑): mitochondrial dysfunction—loss of Δψm (↓); release of cytocromo C, Smac/DIABLO and AIF; Bax ↑, Blc-2 and Mcl-1↓; caspase-3 and -9 ↑; morphologic changes—condensed chromatin, nuclei fragmented and apoptotic bodies; and DNA ladder EGCG (10 µmol/L) + AS2O3 (2 µmol/L) intensified apoptosis and the production of ROS Induced cycle arrest—↑ G1 phase and ↓ S phase |
[45] |
| U937 | EGCG 100 µM (8–24 h) GHF (high molecular weight fraction of green tea) 0.6 mg/mL (8–24 h) |
Induced apoptosis (DNA fragmentation) GHF also induced cycle arrest (↑ G2/M, ↑ p21/Waf1 (mRNA and protein expression) |
[28] |
| K562 | Green tea extract 100 mg/mL (0–24 h) | Induced apoptosis (chromatin condensation, nuclear fragmentation, DNA fragmentation, ↓ Bcl-2, ↑Bax and caspase-3/-8 activation) Induction of cycle arrest (↑ sub G1 peak, ↓DNA content of G1 phase) |
[17] |
| K562 U937 Primary leukemic cells—CML and ALL (Ph+) Normal WBC |
TRE—tea (Camellia sinensis var assamica) root extract 0–15 µg/mL | Induced apoptosis (↓ the rate of cellular DNA synthesis—↓ thymidine incorporation, DNA degradation, apoptotic bodies and membrane blebbing) Induced cell cycle arrest (↑ content of hypoploid DNA and ↓ content DNA in G0/G1 phases—U937 or ↓ cells in S or G2/M phases—K562) |
[19] |
| RAJI | EGCG and synthetic analogs of EGCG (a para-amino group on the D-ring) 25 µM (4–24 h) |
Induced apoptosis (caspase-3 activation, PARP cleavage) and inhibition of proteasome activity (accumulation of proteasome target protein, like Bax, Iκb-α and p27) | [11] |
| MPO-positive myeloid leukemia cell lines: HL60, KASUMI, NB4 and UF-1 MPO-negative myeloid leukemia cell lines: KG1, K652, THP-1 and U937 |
EGCG 0–300 µM (30 min–48 h) |
Induced apoptosis in MPO-sensitive leukemia cells through ROS production | [27] |
| HL60 K562 | EGCG and 5-AZA-CdR | Induced apoptosis through mitochondrial dysfunction—loss of Δψm (↓) and modulation of Bcl-xl (↓) and BAX | [57] |
| HTLV-I-positive ATL cell line: C91-PL HuT-102 HTLV-I-negative cell line: CEM JURKAT |
EGCG 0-400 µM (0–96 h) IC50 (48 h) C91-PL= 310 µM HuT-102 = 350 µM CEM = 272 µM Jurkat = 378 µM |
Induced apoptosis (DNA fragmentation, ↑ pre-G1 phase cells, ↑ p21, p53 and Bax, ↓ Bcl-2α, ↓ TGF-α—cytokine with proliferative activities, ↑ TGF-β2—anti-proliferative and apoptotic effects; DNA fragmentation) | [40] |
| HL60 undifferentiated | EGCG 50 µM (4 h) |
Induced apoptosis detected through the formation of apoptotic bodies and DNA ladder | [29] |
| HL60 V79-4 |
GTP 0–300 µg/mL (0–72 h) IC50 = 49.5 µg/mL (48 h) IC50 = 50.0 µg/mL (72 h) |
Induction of apoptosis detected by nuclear fragmentation; Bcl-2 ↓; PARP cleavage (↑) and pro-caspase-3 ↓ Induced cycle arrest—↑ sub-G1 phase No cytotoxic effects in V79-4 with GTP (48 h) |
[21] |
| HL60 V79-4 | EGCG and EGC 50 µM (24–48 h) EGCG IC50 = 60 µM (48 h) IC50 = 57.7 µM (72 h) EGC IC50 =107.7 µM (48 h) IC50 = 97.5 µM (72 h) |
Induced apoptosis detected through nuclear fragmentation; Bcl-2; and pro-caspase-3 ↓ EGCG > EGC No cytotoxic effects in V79-4 with EGCG or EGC (48 h) |
[20] |
| Primary AML blasts cells HL-60 NB4 |
EGCG 0–40 µmol/L (24–36 h) IC50 = 21.5 µmol/L (24–36 h) IC50 = 30.5 µmol/L (24–36 h) |
Induced apoptosis detected by ↑ of DAPK2 and the level of 67LR expression | [16] |
| NB4 NB4 R1 NB4 R2 Primary APL/leukemia cells |
Catechins 0–400 µM (0–48 h) IC50 < 125 |
Induced apoptosis through ROS production (↑): mitochondrial dysfunction—loss of Δψm; release cytocromo C; Blc-xL ↓; caspase-3, -8 and -9 ↑; PARP cleavage (↑); morphologic changes—condensed chromatin, nuclei fragmented and apoptotic bodies; and ↓ PML/RARα | [33] |
| NB4 | EGCG 0-40 µM (24 h) |
Induced apoptosis through the SHP-1-p38αMAPK-Bax cascade (↑ Bax, SHP-1 (Src homology 1 domain-containing protein tyrosine phosphatase) expression and levels of phosphorylated (p)-p38α MAPK) | [18] |
| JURKAT | EGCG 0–100 µM (0–72 h) IC50 = 82.8 ± 3.1 µM 24 h 68.8 ± 4.0 µM 48 h 59.7 ± 4.8 µM 72 h |
Induced apoptosis through Fas/Fas ligand activation: ↑ Fas expression and caspase-3 ↑ | [39] |
| K562 K652R KCL-22 BaF3/p210 BaF3/p210T3151 Primary bone marrow CML cells |
EGCG 0–100 µmol/L (0–48 h) IC50 = 62.62 µmol/L K562 91.12 µmol/L K562R 53.76 µmol/L KCL-22 12.80 µmol/L BaF3/p210 29.82 µmol/L BaF3/p210T3151 |
Induced apoptosis by regulating Bcr/Abl (degradation)-mediated JAK2/STAT3/AKT (↓) and p38-MAPK/JNK (↓) signaling pathways. Induced autophagy function (↑ Atg5 and LC3), as well as ↓ MMP (mitochondrial membrane potential), ↑ HSP60 (mitochondrial protein marker), histone H3 and AIF (apoptosis-inducing factor) |
[51] |
| HL60 | EGCG 100 µM (5 days) IC50 = 190.4 ± 0.03 µM (5 days) |
Induced apoptosis, ↓ AKT and ↑ CASP3, CASPP8, p21 and PTEN gene expression; ↓ ABCB1 and ABCC1 (genes of multi-drug resistance) | [24] |
| In vivo—Xenograft and systemics model | |||
| Murine myeloid leukemia WEHI-3B JCS cells pre incubated with EGGC in Balb/c mice (injected i.p.) | EGCG 40 µM (4 h) |
Reduction in the tumorigenicity—↓ the leukemic cell growth | [50] |
| APL cells (UF-1) in Nod. Scid mice (xenografted) |
EGCG 10 mM as the sole drink for 12 days |
Reduction in tumor weight and inhibition of cell proliferation. During the treatment, the mice appeared healthy, and there was no change in the tissue organs | [26] |
| APL cells (NB4) in Nude mice (xenografted) | Catechins 10 mM as the sole drink for 21 days |
Reduction in tumor weight and induction of apoptosis During the treatment, the mice appeared healthy, and there was no infiltration in any of the organs |
[33] |
| APL cells (HL60) in NOD. CB17-Prkdcscid/J mice (xenografted) |
GT 100 mg/kg as gavage |
Reduction in tumor weight and induction of apoptosis (↑ cytochrome c ↓ Bcl-2, ↑ Bax and pJNK, ↑ caspase 3), cell cycle arrest (↓ CDK2 and cyclin A and ↑ p21) and autophagy (↑ LC3-II) | [54] |
| hCG-PML/RAR transgenic mice cells in NOD. CB17-Prkdcscid/J mice |
GT 250 mg/kg/d intraperitoneally, for 5 days |
Reduction in spleen weight and induction of apoptosis of blasts in spleen and bone marrow (↑ of caspase-3, -8 and -9) and ↓ CXCR4/HIF-1α pathway in response to ↓ ROS levels | [55] |
| hCG-PML/RAR transgenic mice cells in NOD. CB17-Prkdcscid/J mice |
EGCG 25 mg/kg/d intraperitoneally, for 5 days |
Reduction in spleen weight and induction of apoptosis of spleen cells by modulating Bax (↑), Bad (↑), Bcl-2 (↓) and c-Myc (↓) | [7] |