Table 5.
Control of kinase signaling by berry polyphenols and effects on cell cycle, apoptosis and autophagy
| Polyphenol | Cell line/Dose | Cell cycle arrest | Cell death pathway | Markers | Proposed mechanisms | Kinase pathway | Reference |
|---|---|---|---|---|---|---|---|
| Cyanidin | HS578T/10μM | G2/M | Apoptosis | ↓ CDK1, CDK2, cyclin B, cyclin D PARP cleavage | Caspase-dependant | - | (149) |
| Delphinidin | SMMC7721/150μM | Autophagy | ↑ LC3 II. Inhibited by 3MA and Bafilomysin. No ↑ in caspase activity. | No ER stress. | Class III PI3K | (58) | |
| AU565/40μM | Apoptosis | ↑ PARP cleavage ↓ BCL2, ↑ BAX |
Inhibition of EGFR signaling | PI3K/AKT MAPK |
(142) | ||
| Hep G2/100μM | Apoptosis | ↑ caspase 3, PARP cleavage ↓ BCL2, ↑ BAX |
Oxidative stress mediated | JNK ↑ cJun mRNA; ↑ p-JNK | (54) | ||
| PC3/180 μM | G2/M | Apoptosis | ↑ caspases, PARP cleavage, BAX, p21, p27 ↓ BCL2 |
Inhibition of NFkB signaling | IKK⌈ (↓ p-IKK) | (150) | |
| Quercetin | MCF-7/150μM | S | Apoptosis | ↓ BCL2, Cyclin A, B, procaspase 8,12 and CDK2 ↑ PERK, GRP78, CHOP/GADD153, p53 and p57 ↓ mitochondrial membrane potential ↑ Caspases 6,8,9 |
ER stress and UPR ↑ Ca2+ influx, ↔ ROS |
- | (151) |
| MCF-10A, MDA-MB-231/100μM | G1 | Apoptosis | ↑ p-p53, p21 ↓ BCL-xl, cyclin B1 ↔ PTEN, Cyclin D, p27, cdc2 and p-cdc2 |
P53 dependant | - | (152) | |
| AGS, MKN28 | Autophagy | ↑ LC3 II, AVO | Beclin-1 mediated, HIF1-α | AKT/mTOR | (153) | ||
| Kaempferol | MCF-7, MDA-MB-231/30μM | G1 | Apoptosis | ↑ PARP cleavage ↑ MEK1 and p-ELK1 |
ROS mediated | ERK1/2 (sustained activation) | (55) |
| Ellagic acid (Urolithins) | Caco-2/10μM | G1 | Apoptosis | ↓ cyclins A and B, BCL-xl ↑ Cyclin E |
Fas-dependent Caspase 8-independent, mitochondrial membrane mediated | ERK1/2 (↑ activation) | (154–155) |
| Resveratrol | MDA-MB-231/50μM | Apoptosis | ↓ BCL2 ↔ BAX, BAD, BCL-xl JNK and p38 inhibition |
MEK1/2 mediated | ERK1/2 (sustained activation) | (56) | |
| MCF-7/150μM | Apoptosis | ↓ BCL2 ↔ caspase 8 activity ↔ PARP cleavage ↓Δ ψm |
ROS mediated NFkB dependent |
PI3K | (140) | ||
| MCF-7vc and MCF-7casp3/64μM | Autophagy/Apoptosis | Cell death in MCF-7vc ≫MCF-7Cap3 Caspase expression ↓ autophagy LC3 II and GFP-LC3 not ↓ by BECN1 or hvP534 knockdown |
Non-canonical BECN1 – independent atg7-dependent | AKT/mTOR (↓ p-AKT; inhibition of mTOR) | (156) | ||
| Pterostilbene | T24 and T24R/100μM) | S (50–75μM) G1 (100μM) |
Apoptosis/Autophagy | ↓ Cyclins A, B, D1, p-Rb ↓ caspase 3 activity ↑ LC3 II, AVO ↑ BCL2. BCL-xl ↔ BAX, BAD |
BECN1-dependent (3MA and BECN1 shRNA inhibit action) | AKT/mTOR (↓ p-AKT/mTOR) ERK 1/2 activation |
(59) |
Cell line origins: Breast- AU565, HS578T, MCF-10A, MCF-7, MDA-MB-231, MCF-7vc, MCF-7casp8; Liver- SMMC7721, HepG2; Gastric cancer- AGS, MKN28; Prostate- PC3; bladder- T24, T24R; Colon- Caco-2.
Abbreviations: CDK- cyclin dependent kinase; PARP- Poly (ADP-ribose) polymerase; BCL2- B-cell lymphoma 2; BAX- Bcl-2 associated X protein; BAD- Bcl-2 associated death promoter; PERK- Protein kinase RNA-like endoplasmic reticulum kinase; GRP78- glucose regulated protein 78 (also called- BiP or HSPA5); CHOP- ccaat enhancer binding protein homologous protein; PTEN- phosphatase and tensin homolog; cdc- cell division cycle; LC3- microtubule associated protein light chain 3; AVO- autophagic vacuoles; ELK- E twenty-six (ETS)-like transcription factor 1