Table 5.
Studies demonstrating the radiomodulatory effects of resveratrol.
| Study | Cancer Type/Cell Line | Radiation Dose | Resveratrol Dose/Conc. | Major Findings | Proposed Mechanisms |
|---|---|---|---|---|---|
| Zoberi I et al. 2002 [216] | Human cervical carcinoma cell lines, HeLa and SiHa | Ionizing Radiation (IR) 2–8 Gy | 10 or 25 μM for 4–48 h | RESV enhanced tumor cell killing by IR in a dose-dependent manner | Inhibition of COX-1 |
| Baatout S et al. 2004 [217] | HeLa (cervix carcinoma), K-562 (chronic myeloid leukemia) IM-9 (multiple myeloma) |
0–8 Gy | 0–200 μM started 1 h before the irradiation | RESV can act as a radiation sensitizer at high concentrations | Induced apoptosis and inhibition of cell growth |
| Baatout S et al. 2005 [218] | Human leukemic cell line, EOL-1 | 0, 2, 4, 6, or 8 Gy | 0–200 μM | Depending on the concentration, RESV could enhance radiation-induced apoptosis | Induced apoptosis and inhibition of cell growth |
| Liao HF et al. 2005 [219] | Human non-small cell lung cancer NCI-H838 | 0.5, 1, 2, and 3 Gy | 6.25–50 μM | RESV sensitized NCI-H838 to radiation in a concentration-dependent manner | NF-κB inhibition and S-phase arrest |
| Scarlatti F et al. 2007 [220] | DU145 prostate cancer cells | 0.5–2.0 Gy/day for 3 consecutive days | 0.5–32 μM for 72 h | RESV significantly enhanced radiation-induced cell death | RESV potentiated ionizing radiation-induced ceramide accumulation, by promoting its de novo biosynthesis |
| Lu KH et al. 2009 [221] | Medulloblastoma-associated cancer stem cells | Ionizing radiation 0–10 Gy | 0, 10, 50, 100, and 150 μM for 48 h | RESV 100 μM enhanced the radiosensitivity | Anti-proliferative properties |
| Kao CL et al. 2009 [222] | CD133-positive/negative cells derived from atypical teratoid/rhabdoid tumors | 2 Gy | 150 μM | RESV enhanced IR-mediated apoptosis | ↓ Proliferation |
| Rashid A et al. 2011 [223] | Androgen-insensitive (PC3), sensitive (22RV1) prostate cancer cells | IR (2–8 Gy) | 2.5–10 μM | RESV enhanced IR-induced nuclear aberrations and apoptosis in cancer cells | RESV enhanced IR activation of ATM and AMPK but inhibited basal and IR-induced phosphorylation of Akt |
| Fang Y et al. 2012 [224] | Prostate cancer cell line, PC-3 | 2–8 | 2–10 μM | RESV augmented radiation-induced inhibition of cell proliferation and reduction of cell survival | Increased apoptosis and senescence |
| Yang YP et al. 2012 [225] | Primary Glioblastoma cells | In vitro: 0, 2, 4, 6, 8, and 10 Gy | 100 μM for 24 h | RESV induced apoptosis and enhanced radiosensitivity of glioblastoma cells | Inhibiting the STAT3 Axis |
| Tak JK et al. 2012 [226] | Mouse colon carcinoma CT26 and mouse melanoma B16F10 cells | 15 Gy γ-irradiation | 10 and 20 µM | RESV sensitized the cancer cells to radiation-induced apoptosis | Increased ROS |
| Fang Y et al. 2012 [227] | Prostate cancer cell lines (PC-3 cells and DU145 cells) | 2, 4, and 8 Gy | 0–50 μM for 24 h | Combination of radiation and RESV additively/synergistically decreased survival of PCA | ↑ Apoptosis ↑ Perforin and granzyme B expression |
| Yang YP et al. 2012 [225] | Glioblastoma multiforme (GBM)-derived CD133+ radioresistant tumor-initiating cells (TIC) | 0, 2, 4, 6, 8, and 10 Gy | 100 μM for 24 h | RESV could significantly improve the survival rate and synergistically enhance radiosensitivity of radiation-treated GBM-TIC | STAT3 Pathway by suppressing STAT3 signaling. ↓ Bcl-2 and survivin expression |
| Fang Y et al. 2013 [228] | Radio-resistant human melanoma lines (SK-Mel-5 and HTB-65) | 1, 2, and 4 Gy | 0–50 μM for 24 h | RESV enhanced radiation sensitivity of melanoma cells | ↓ Proliferation ↓ Expression of proproliferative molecules (cyclin B, cyclin D, cdk2 and cdk4) ↑ Apoptosis ↓ Expression of anti-apoptotic molecules (FLIP, Bcl-2, and survivin) |
| Luo H et al. 2013 [229] |
Human non-small cell lung cancer (NSCLC) cell lines A549 and H460 | (0–8 Gy) of irradiation at 4 h after RESV pre-treatment | 20 μM | RESV sensitized the cancer cells to radiation-induced cell death | Enhancing IR-induced premature senescence via increasing ROS-mediated DNA damage |
| Magalhães VD et al. 2014 [230] | Human rhabdomyosarcoma cells (RD) |
50 and 100 Gy | 15, 30, and 60 μM for 24 h | RESV 15 μM protected cells and had cytotoxic effect at 60 μM | RESV at 60 μM could inhibit cell growth and induce apoptosis |
| Heiduschka G et al. 2014 [231] | Merkel cell carcinoma MCC13 and MCC26 cells | 1, 2, 3, 4, 6, and 8 Gy | 7.5 and 15 μM | RESV and irradiation led to synergistic reduction in colony formation compared to irradiation alone | No specified mechanism was mentioned |
| Antienzar AN et al. 2014 [232] |
Oral squamous cell carcinoma PE/CA-PJ15 cells |
1, 2.5, and 5 Gy | 5, 10, 25, 50, and 100 μM for 24, 48, and 78 h | RESV increased radiation-induced cell death, apoptosis and migration in conc and time-dependent manner | Induce apoptosis and cell migration |
| Wang L et al. 2015 [233] |
Glioma stem cell line, SU-2 For the in vivo studies: Five-week-old male nude (BALB/c) mice |
In vitro: 0, 2, 4, 6 Gy In vivo: IR (X-ray, 6 Gy) twice on day 3 and day 9 | In vitro: 75 μM In vivo: 150 mg/kg every other day for 2 weeks |
RESV enhanced radiation-induced effects both in vitro and in vivo | Inhibition of self-renewal and stemness Induction of autophagy, promotion of apoptosis, and prevention of DNA repair |
| Baek SH et al. 2016 [234] |
Squamous cell carcinoma of the head and neck FaDu cells | 1, 5, and 10 Gy | 50 and 100 2 h pretreatment and 24 h after radiation |
RESV potentiated the effect of radiation on FaDu cells | Inhibition of STAT3 signaling pathway through the induction of SOCS-1 |
| Chen YA et al. 2017 [235] |
Prostatic cancer LAPC4-KD cells In vivo: Male nude BALB/c mice |
In vitro: 2 Gy In vivo: 12 Gy delivered in 3 doses on day 0, 3, and 7 |
In vitro: 25 μg/mL (100 μM) for 24 h In vivo: 5 mg/kg |
RESV inhibited the proliferation and increased radiosensitivity of radioresistant cells. Moreover, RESV inhibited tumor growth in vivo | Induce apoptosis ↑ Caspase-3 |
| Tan Y et al. 2017 [236] |
Nasopharyngeal cancer, CNE-1 cells in vitro BALB/c nude mice in vivo |
In vitro: 0, 2, 4, 6 Gy In vivo: 4 Gy |
In vitro: 50 μM for 24 h In vivo: 50 mg/kg/day On day 8, mice were treated i.p. with RESV or vehicle until the completion of the experiment. On day 12, mice were irradiated once a day for consecutive 3 days. Mice were sacrificed on day 28 to measure tumor volume and tumor weight |
RESV sensitized CNE-1 cells to radiation in vitro and in vivo | Downregulating E2F1 and inhibiting p-AKT |
| Ji K et al. 2018 [215] |
Human lung cancer cell lines A549 and H460 | 0, 2, 4, or 6 Gy irradiation | 50 µM for 24 h | RESV reduced radiation-induced apoptosis (protected the cancer cells from radiation) | Activation of Sirt1 protects cancer cells from radiation |
| Voellger B et al. 2018 [212] | Rodent GH3 and TtT/GF pituitary adenoma cells | 0–5 Gray | 10 and 100 μM for 2 h before radiation and further incubated for 48–72 h | Combination of RESV and irradiation significantly decreased cell viability | Induce cell death |
| Banegas YC et al. 2018 [211] |
Human lung cancer cell line A549 | 4 and 16 Gy X-ray | 15 and 60 μM for 24 and 120 h | RESV 60 μM had a radiosensitizing effect | RESV 15 μM had no effect on tumor cells, but was radioprotective in CHO-k1 cells |
Akt, Protein Kinase B; AMPK, Adenosine Monophosphate-Activated Protein Kinase; ATM, Ataxia-Telangiectasia Mutated; BCL, B Cell Lymphoma; Cdk, cyclin-dependent kinase; E2F1, E2F Transcription factor 1; FLIP, FLICE-like inhibitory protein; IR, ionizing radiation; NF-κB, nuclear factor kappa B; PCA, prostate cancer; Sirt1, Sirtuin 1; SOCS, Suppressor of cytokine signaling; STAT3,Signal transducer and activator of transcription 3; IR, Ionizing Radiation; RESV, Resveratrol; ROS, Reactive Oxygen Species; ↑, increase; and ↓, decrease.