Table 1.
Effects of resveratrol (RSV) as a single agent against lung cancer: in vitro studies.
| Cancer Cell | Dose/Duration | Findings | Mechanism | Reference |
|---|---|---|---|---|
| A549 and H460 | 100 μM RSV for 24 h | ↓growth | ↑LC3 ↑PELP1 accumulation in autophagosomes with GFP-LC3 |
[22] |
| A549 | 25, 50, 100 μM RSV for 48, 72, 96 h | ↑apoptosis ↑cell cycle arrest |
↑p53 and p21 ↑caspases ↑disruption of the mitochondrial membrane complex G1 cell cycle arrest Altered expression of cyclin A, chk1, CDC27 and Eg5 ↓Smad activators 2 and 4 ↑repressor Smad 7 |
[23] |
| A549, A427 and NCI-H23 | 20, 50, 100 μM RSV for 2, 4 or 8 h | ↓PI3K pathway ↓tumor formation |
↓mTOR phosphorylation | [24] |
| BEAS-2B | 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) + 0.01, 0.05, 0.1, 0.5, 1, 5, 10 μM RSV for 6 h | RSV is a potent repressor of TCDD inducible gene transcription in estrogen receptor (ER+) human lung cancer | RSV completely abrogates TCDD-induced CYP1A1 gene transcription | [25] |
| A549 | 12.5, 25, 37.5, 50, 62.5, 75, 87.5, 100 μM DHS for 48 h | ↓cell proliferation | ↑ROS species Sub G1 formation (cell cycle arrest) ↓mitochondrial membrane potential ↓Poly (ADP-ribose) polymerase degradation ↑intracellular acidic vacuoles ↑LC3-II formation and intracellular GFP-LC3 aggregation |
[26] |
| SPC-A-1 | 25 μM, 50 μM or 100 μM RSV, for up to 96 h | ↓proliferation ↑apoptosis ↑cell cycle arrest |
↑caspase-3 ↓survivin levels |
[27] |
| A549 | 60, 120 μM RSV for 24 h | Altered miRNA expression (miRNA is involved in initiating lung cancer) | - | [28] |
| H1299 | 10 mM–500 mM RSV, for 4 h | ↓glycolysis | ↓mono-ubiquitination of histone H2B | [29] |
| 16HBE-T and H460 | 12.5, 25, 50 μM RSV for 48 h | ↓cell viability ↓cell proliferation. ↑cell cycle arrest |
↑miR-622 expression ↑G0 cell cycle arrest K-ras is downstream target of miR-622 |
[30] |
| A549 | 1.25, 2.5, 5, 7.5, 10 μM Trimethoxyl Stilbene (TMS) for 48 h | TMS inhibited proliferation and induced apoptosis in a dose-dependent manner | ↑Up-regulation and cleavage of caspase-3 ↑IKB ↓NF-κB, STAT3, STAT5b and JAK2 signal transduction |
[31] |
| ASTC-A-1 | 0 μM–125 μM RSV for 48 h | Induction of apoptosis | ↑caspase-3 and-9 | [32] |
| A549, H1299 and H460 | 100, 200, 300, 400, 500 μM RSV for 5 min, 24, 48 h | ↓cell viability (p53 dependent) Transient transfection of WT p53-GFP gene caused H1299 cells to become more responsive to the pro-apoptotic properties of RSV |
↑caspase-9 and -7 activation ↑PARP cleavage |
[33] |
| A549 | 20, 40, 60, 80, 100 μM Pterostilbene for 48 h | ↓cell growth. ↑apoptosis. Autophagosome accumulation Lysosomal membrane permeabilization |
HSP70 protein deficiency showed high susceptibility to pterostilbene. | [34] |
| LLC | 50 μM RSV for 24 h | ↓18F-FDG uptake | ↓glycolytic flux and Glut-1 expression ↑ROS ↓HIF-1a expression ↓Akt activation |
[35] |
| A549 and H460 | 10, 20, 50 μM RSV for 10 to 12 days | Inhibition of growth in a dose-dependent manner. No effect on expression of cleaved PARP and activated caspase-3, suggesting that low dose RSV treatment inhibits growth in an apoptosis-independent mechanism | (1) Increase in SA-B-gal (2) Increased p53 and p21 expression (3) Decreased EF1A expression (4) Increased double-stranded DNA breaks (5) Increased ROS (6) Upregulated Nox5 expression |
[36] |
| A549 | 20 μM Benzo(a)pyrene for 48 h pre-treatment + 10 μM RSV for 24 h | Decreased cell viability. Increased p53 levels. Cell cycle arrest. Apoptosis | (1) Down-regulation of Bcl-2 expression (2) Decreased cyclin D expression (3) Increased p21 expression (4) Increased TRAIL receptors 1 and 2 expression (5) Down-regulation of NF-KB and IKK1 expression (6) Induction of G2/M cell cycle arrest |
[37] |
| A549 | 0 μM–40 μM RSV, for 48 h | Decreased proliferation and EMT. Suppression of cell adhesion | Inhibition of the morphological changes of TGF-β1 induced EMT. | [49] |
| A549 | 2, 4, 8, 16, 32, 64 μM RSV for 48 h | RSV exerts dose-dependent cell inhibition | Activation of caspase-3 | [38] |
| CL1-5, A549, H322 and H1435 | 20 μM RSV, for 48 h | Suppression of tumor growth | Downregulation of Akt, I-κB and NF-κB | [39] |
| A549 and H1299 | 0.02, 2% red wine (equivalent to 4, 400 nM RSV) and 0.5, 2% white wine | Inhibition of cell proliferation. Wine mixture induced effects that were only reproducible at 50 μM RSV treatment alone | (1) Reduced basal and EGF-stimulated Akt and Erk phosphorylation (2) Increased p53 expression and phosphorylation |
[50] |
| H1975 | 20, 40, 60, 80 nM TMS for 24 h | Elevated intracellular calcium levels in Gef resistant NSCLC. Anti-proliferative effect only in G-R NSCLC but not normal NSCLC and normal lung epithelial cells | (1) Decreased EGFR phosphorylation and activation (2) Induction of caspase-independent apoptosis and autophagy by directly binding to SERCA and causing ER stress and AMPK activation (3) Suppressed the mTOR pathway (4) Increased JNK activity |
[40] |
| A549 | 5.5 μM–175.2 μM RSV, for 24h | Inhibition of growth | Induction of caspase-3 | [41] |
| A549 | 0.05, 0.10, 0.23 μM RSV + 8.14 μg/mL NP for 24 h pre-treatment followed by 100 μg/mL Cigarette Smoke Condensate (CSC) for 48 h | RSV at all doses attenuated CSC-induced DNA fragmentation. NPs dramatically increased RSV induced apoptosis in CSC-treated cells | Not provided, but results indicate that NPs are capable of increasing the efficacy of lipophilic drugs such as RSV | [42] |
| H727 | 25 μM RSV for 48 h | Decreased cell proliferation and cell viability. Induction of cell cycle arrest | AK001796 a long noncoding RNA (lncRNA) knockdown by resveratrol | [51] |
| A549 | 25, 50, 100, 150 μM RSV for 24, 48, 72 h | Inhibition of proliferation in a dose-dependent manner. G0/G1 cell cycle arrest. | (1) Upregulation of p53 nuclear expression (2) Downregulating expression levels of cyclin D1, CDK4, CDK6 (3) Upregulation of p21, p27 which are CDK inhibitors |
[44] |
| A549 | 50 μM RSV for 12, 24, 48, 72, 96 h | P62 links RSV induced autophagy to apoptosis. P62 inhibits apoptosis by inhibiting Fas/Cav1 complex formation. | (1) RSV degraded P62 allowing Fas/Cav1 complex formation (2) Fas/Cav1 activated caspase-8-mediated Beclin-1 cleavage, resulting in c-terminal Beclin-1 fragment translocation to the mitochondria to initiate apoptosis |
[32] |
| A549 | 10, 20, 40, 80 μM THS for 12 h | ↑apoptosis and autophagy (dose dependent) | ↑cleaved PARP ↑caspase-3 and -9 ↓Bcl-2 ↑LC3-II accumulation ↓mTOR pathway ↑ROS levels |
[45] |
| A549 | 50 μM RSV pre-treatment for 4h followed by H2O2 treatment (50–1000 μM) with or without RSV for 0.5, 1, 2, 3, 8, 16 and 24h | RSV-loaded nanoparticles restored H2O2 induced ROS levels | ↑RSV uptake ↑Nrf2-Keap1 signalling Accumulation of Nrf2 in abundance |
[46] |
| LLC | 1, 2.5, 5, 7.5, 10 μM DHS for 24 h | ↓LLC cell growth | ↓cell cycle progression ↓cell numbers arresting at G1 accumulation of pre-G1 events correlated with apoptotic behavior ↓LLC cell migration and matrigeal invasion |
[47] |
| CEM and A549 | 1, 5, 10 and 20 μM for 48 and 72 h | ↓proliferation ↑apoptosis | ↓tubulin polymerization G2/M cell cycle arrest at 12–18 h period ↓mitochondrial membrane potential ↑caspase-3 and -9, parp-cleavage |
[48] |
RSV (Resveratrol); PARP (Poly (ADP-ribose) polymerase); LLC (Lewis lung carcinoma); ROS (Reactive oxygen species); NRF-2 (nuclear factor erythroid 2–related factor 2); Bcl-2 (B-cell lymphoma 2); LC3-II (light chain 3-II); mTOR (mechanistic target of rapamycin); CDK4 (Cyclin-dependent kinase 4); CSC (cigarette smoke condensate); H2O2 (hydrogen peroxide); JNK (Jun N-terminal kinase); SERCA (sarco/endoplasmic reticulum Ca2+-ATPase); NSCLC (non-small cell lung cancer); EGFR (Epidermal growth factor receptor); Akt (Protein kinase B); Erk (extracellular-signal-regulated kinase); Gef (Guanine nucleotide exchange factor); EMT (Epithelial–mesenchymal transition); TRAIL (TNF-related apoptosis-inducing ligand); Nox5 (NADPH Oxidase 5); EF1A (Elongation factor 1-alpha); Glut-1 (Glucose transporter 1); SA-B-gal (Senescence-associated beta-galactosidase); HIF-1a (Hypoxia-inducible factor 1-alpha); 18F-FDG (18F-fluorodeoxyglucose); HSP70 (Heat Shock Protein 70); JAK (Janus activated kinase); STAT (signal transducer and activator of transcription); WT (wild type); miR-622 (microRNA-622); NF-KB (nuclear factor-KB); TMS (Trimethoxyl Stilbene); IKB (inhibitor of KB); DHS (Dehydrosilybin); GFP-LC3 (green fluorescent protein-light chain 3); TCDD (tetrachlorodibenzo-p-dioxin); CYP1A1 (cytochrome p450 1A1); PI3K (Phosphoinositide 3-kinase); CDC27 (cell division cycle protein 27); LC3 (light chain 3 protein); chk1 (checkpoint kinase 1); PELP1 (Proline, Glutamate and Leucine Rich Protein 1); ↑ (increase); ↓ (decrease).