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. 2017 Nov 10;9(11):1231. doi: 10.3390/nu9111231

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).