Critical role of mitochondria in programmed cell death leads to the design of mitochondriotropic agents as a strategy in regulating apoptosis. For anticancer therapy, stimulation of proapoptotic mitochondrial events in tumor cells and their suppression in surrounding normal cells represents a promising paradigm for new therapies. Different approaches targeting regulation of components of mitochondrial antioxidant system such as Mn-SOD demonstrated significant antitumor efficiency, particularly in combination therapy. This review is focused on a newly discovered early stage of mitochondria-dependent apoptosis -oxidative lipid signaling involving a mitochondria-specific phospholipid cardiolipin (CL). Cytochrome c (cyt c) acts as a CL-specific peroxidase very early in apoptosis. At this stage, the hostile events are still secluded within the mitochondria and do not reach the cytosolic targets. CL oxidation process is required for the release of pro-apoptotic factors into the cytosol. Manipulation of cyt c interactions with CL, inhibition of peroxidase activity, and prevention of CL peroxidation are prime targets for the discovery of anti-apoptotic drugs acting before the "point-of-no-return" in the fulfillment of the cell death program. Therefore, mitochondriatargeted disruptors and inhibitors of cyt c/CL peroxidase complexes and suppression of CL peroxidation represent new strategies in anti-apoptotic drug discovery.

Gastric cancer (GC) is the most common cause of morbidity and mortality because of cancer. Medicinal plants containing polyphenolic compounds have gained importance in anticancer treatment. In this context, carvacrol is a main component of many plants in the family Lamiaceae that are frequently used in folk medicine and a good candidate to investigate for GC treatment. The present study aimed to explore the cytotoxic, genotoxic, apoptotic, and reactive oxygen species (ROS)-generating effects of carvacrol on gastric adenocarcinoma in vitro. For these purposes, human gastric adenocarcinoma (AGS) cells were used and analyzed after 24 h of exposure to carvacrol with different concentrations. The cytotoxicity, ROS generation, glutathione (GSH) level, and genotoxicity were investigated by the ATP cell viability assay, 2',7'-dichlorodihydrofluorescein-diacetate assay, GSH/GSSG-Glo assay, and comet assay, respectively. Apoptosis induction was detected by acridine orange/ethidium bromide staining and western blotting at below the half-maximal growth inhibitory concentration value. Carvacrol showed cytotoxic, genotoxic, apoptotic, ROS generating, and GSH-reducing effects on AGS cells in a dose-dependent manner. There was a close negative relationship between cell viability and ROS level. Carvacrol inhibited the proliferation of AGS cells, suggesting that it could be a novel and strong anticancer agent against the human gastric adenocarcinoma. These results support the interest of natural diet components in the development of therapeutic products for diseases.

The aim of this study was to observe effects of ascorbic acid application on pain, performance status, and survival time in cancer patients. A retrospective cohort of 39 patients with bone metastases treated with radiotherapy was identified. All patients were radiotherapy-resistant. Fifteen patients who received chemotherapy, and 15 patients who received an infusion of 2.5 g ascorbic acid were included in the study. Nine control patients were treated with neither chemotherapy nor vitamin C. Eastern Cooperative Oncology Group Performance Status Scale and Visual Analog Scale were used to determine performance status and pain assessments. Survival time and rate in patients were defined. Statistical analyses were performed to compare the results of groups. Performance status was increased in 4 patients of vitamin C group and 1 patient of chemotherapy group, whereas performance status in control group was decreased. A median reduction of 50% in pain was observed among the patients in the vitamin C group. Median survival time was 10 mo in patients receiving ascorbic acid, whereas the chemotherapy and control groups had a median survival of 2 mo. Intravenous vitamin C application seems to reduce pain in patients in comparison to other patients who did not receive it. Patient performance status and survival rate were increased using vitamin C.

Carvacrol is a natural phenolic compound found in essential oils of Lamiaceae species. In the present study, an attempt has been made to elucidate the mechanism behind the anti-cancer potential of carvacrol on human gastric adenocarcinomas (AGS) by comparing its effects on cancer cells AGS to those on normal human fibroblast (WS-1) cells, in vitro. Cytotoxicity, reactive oxygen species (ROS) generation, glutathione (GSH) levels, genotoxicity, and apoptotic effects of carvacrol (0-600 µM) were studied in both cell lines. Additionally, the effect of high dose carvacrol (100 mg/kg BW) on the oxidative status was investigated in vivo. For this purpose, carvacrol was administered orally to male Wistar rats over a period of 60 days. Rats were weighed regularly. At the end of the experiment, rats were euthanized. Blood and stomach tissues were collected for biochemical and pathological examinations. The in vitro results showed significant differences in cell viability of AGS compared to WS-1 cells exposed to carvacrol. Also the extent of ROS generation, GSH reduction and DNA damage differed significantly between the cell lines studied (P ≤ 0.001). The differences observed were statistically significant at all concentrations applied (P ≤ 0.001). The results found in AGS cells were mirrored in the pathohistological findings obtained from animals of the in vivo experimental group. Changes in body weight, and oxidative stress index for plasma and stomach tissues of animals in this group were found to differ statistically significant from those found in the control group of Wistar rats (P ≤ 0.001). The data obtained from our present study uncovered that carvacrol has the potential to cause toxic effects in both, AGS and WS-1 cells but more effectively in cancer cells than in normal cells. The carvacrol-mediated responses observed in the in vitro and in vivo experiments presented suggest a double-edged pro-oxidative effect. Via this mechanism carvacrol induced cytotoxicity, apoptosis, and DNA damage in a dose-dependent manner in both cancer and normal cells and these activities were higher in cancer cells than those of normal cells.

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Phenolic compounds of essential oils from the family Lamiaceae are commonly used substances in the food industry because of their flavouring, antimicrobial and antioxidant properties. In this context, it has become important to have healthy and safe products for consumers who are exposed to these phenolic compounds. The present study was aimed to investigate the toxic effects of carvacrol, thymol and their mixture on human gastric carcinoma (AGS) cells. Cells were analyzed after 24 h of exposure to different concentrations of carvacrol, thymol and their mixture by the ATP cell viability, 2',7' dichlorodihydrofluorescein diacetate (H2DCF-DA), reducte glutatione/oxide glutathione ((GSH)/GSSG-Glo) and comet assays. Apoptosis induction was studied by acridine orange/ethidium bromide staining and western blotting. Carvacrol, thymol and their mixture induced cytotoxicity, genotoxicity, apoptosis, increased reactive oxygen species (ROS) and decreased GSH levels after 24 h of their exposure in a dose-dependent manner. A close negative relationship was found between cell viability and ROS generation. We examined dose-dependent cytotoxic effects of carvacrol, thymol and their mixture in human AGS cells. Increased intracellular ROS causes oxidative stress in cells. The results indicated that these compounds should be used carefully in the food industry.

The concept of hormesis includes a biphasic cellular dose-response to a xenobiotic stimulus defined by low dose beneficial and high dose inhibitory or toxic effects. In the present study, an attempt has been made to help elucidate the beneficial and detrimental effects of thymol on different cell types by evaluating and comparing the impact of various thymol doses on cancerous (AGS) and healthy (WS-1) cells. Cytotoxic, genotoxic, and apoptotic effects, as well as levels of reactive oxygen species and glutathione were studied in both cell lines exposed to thymol (0–600 µM) for 24 h. The results showed significant differences in cell viability of AGS compared to WS-1 cells exposed to thymol. The differences observed were statistically significant at all doses applied (P ≤ 0.001) and revealed hormetic thymol effects on WS-1 cells, whereas toxic effects on AGS cells were detectable at all thymol concentrations. Thymol at low concentrations provides antioxidative protection to WS-1 cells in vitro while already inducing toxic effects in AGS cells. In that sense, the findings of the present study suggest that thymol exerts a dose-dependent hormetic impact on different cell types, thereby providing crucial information for future in vivo studies investigating the therapeutic potential of thymol.

Carvacrol is a dietary polyphenol from Lamiaceae plants that has been shown to possess a wide range of biological activities including antioxidant and antitumor effects. This study aimed to investigate its anti-inflammatory and antioxidant effects on N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) induced gastric carcinogenesis in Wistar rats. Forty-nine rats were randomly assigned to four treatment and three control groups. Over 60 days, MNNG (200 mg/kg BW) was orally applied to animals of groups 1–5 while the rats in groups 2–5 also received different doses of carvacrol (10, 25, 50, and 100 mg/kg BW, respectively) until the end of the experiment. Group 6 rats were treated with 100 mg/kg BW carvacrol and no MNNG whereas group 7 was the control group without any treatment. After the euthanasia of all rats, the inflammatory cytokines and oxidative stress parameters were assessed in the blood and tissues. The expression of caspase 9, Bax, and Bcl-2 proteins in the stomach tissues were investigated through histopathological examinations. Statistically significant differences were observed in the body weight, oxidative stress, and inflammation parameters of groups 1 to 6 compared to group 7 (p ≤ 0.001). Animals in MNNG groups 2 and 3 treated with the low dose carvacrol (10 and 25 mg/kg BW) showed significantly reduced oxidative stress, inflammation, and apoptotic effect compared to animals of the MNNG groups receiving increased doses of carvacrol (50 and 100 mg/kg BW) or no carvacrol. Rats exposed to MNNG exhibited gastric cancer cells in several areas. In the MNNG group receiving 100 mg/kg BW carvacrol, the inflammatory cell infiltration was observed in gastric mucosal and submucosal areas whereas MNNG rats supplemented with 10 and 25 mg/kg BW carvacrol showed no pathological alterations of the gastric cells. The results of this study indicate that significant antioxidant and anti-inflammatory effects induced by carvacrol at doses of 10 and 25 mg/kg BW interfered with gastric carcinogenesis induced by MNNG in Wistar rats as well as provide hepatoprotection. However, high doses of carvacrol (50 and 100 mg/kg BW) increased oxidative stress, inflammation, and apoptosis.