Apoptotic effects of ε-viniferin in combination with cis-platin in C6 cells

Abstract

Glioblastoma (GBM) is one of the most common and lethal forms of primary brain tumors in human adults. Treatment options are limited, and in most cases ineffective. Natural products are sources of novel compounds endowed with therapeutic properties in many human diseases like cancer. ε-viniferin is a resveratrol dimer and well known for having antiproliferative and apoptotic effects on cancer cells. Cisplatin is a platinum containing anti-cancer drug. In this study, we aimed to investigate antiproliferative and apoptotic effects of using cis-platin and ε-viniferin alone or in combined treatment of C6 cells. Cell proliferation was detected by WST-1. Mitochondrial membrane potential changes in the cells (ΔΨm) were evaluated using cationic dye JC1. Apoptotic index which is a hallmark of late apoptosis was detected by using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method and apoptotic alterations were observed by transmission electron microscope (TEM). Activation of caspase-8, -9, -3 in C6 cells at various incubation periods was measured by flow cytometer. Apoptotic index increased at highest level in only combined treatment cells (91.6%) after 48 h incubation. These results were supported by TEM images. Caspase-8 activation in C6 cells increased to a maximum (12.5%) after 6 h by using combined cis-platin/ε-viniferin treatment (13.25/95 μM). Caspase-9 was activated at 44.5% after combined treatment for 24 h. This rate is higher than using cis-platin (14.2%) or ε-viniferin (43.3%) alone. The combined 13.25 μM/cisplatin and 95 μM ε-viniferin treatment caused maximum caspase-3 activation in C6 cells (15.5%) at the end of the 72 h incubation. In conclusion, it was observed that caspase-8, -9, -3 activation which was determined in vitro, trigerred apoptotic mechanism in C6 cells by using low concentrations of combined cis-platin and ε-viniferin.

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review

“…RES enhanced the sensitivity of these highly resistant cells to TMZ via activation of the DNA double strands/pATM/pATR/p53 pathway, leading to the activation of apoptosis. Additionally, RES promoted the differentiation of GIC involving p-STAT3 inactivation [139]. A RES dimer, ε-viniferin, has been shown to augment the apoptosis of the GBM cell line induced by another chemotherapeutic agent, cisplatin, under in vitro conditions through the activation of caspases 3, 8, and 9 [140].…”

Resveratrol as Chemosensitizer Agent: State of Art and Future Perspectives

“…Further studies indicate that GBM-initiating cells (GICs), which display stem cell properties, are involved in tumor resistance to TMZ; RSV has been shown to enhance the sensitivity of GICs to TMZ via activation of the DNA double strands/pATM/pART/p53 pathway, inducing apoptosis [ 54 ]. Moreover, a RES dimer, ε-viniferin, has been shown to increase apoptosis of the GBM cell line, induced by cisplatin through the activation of caspase 3, 8 and 9 [ 55 ]. Another mechanism of TMZ resistance is the expression of the protein MGMT.…”

Toxicological Evaluation of Piceatannol, Pterostilbene, and ε-Viniferin for Their Potential Use in the Food Industry: A Review

“…The main results of these studies are described in Table 6 . After exposure to 100 µM for 24 h, and 95 µM and 130 µM for 48 h different cancer cells (HL-60 and C6) suffered chromatin condensation, nuclear fragmentation and contraction [ 96 , 104 ]. Thus, it seems that a prolonged exposure to this compound does not result in more damage.…”

“…However, no information about the mutagenic potential of the substance was reported for this assay. In addition, more recent studies have demonstrated that ε-viniferin produces DNA damage in the A431 cell line by the comet assay [ 115 ] and the C6 cell line by the TUNEL assay [ 104 ].…”