Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant action. Thus, melatonin has proven useful in the treatment of tumors in association with chemotherapeutic drugs. This study was performed to evaluate the effect of melatonin on the cytotoxicity and apoptosis induced by three different chemotherapeutic agents, namely 5-fluorouracil (5-FU), cisplatin, and doxorubicin in the rat pancreatic tumor cell line AR42J. We found that both melatonin and the three chemotherapeutic drugs induce a time-dependent decrease in AR42J cell viability, reaching the highest cytotoxic effect after 48 hr of incubation. Furthermore, melatonin significantly augmented the cytotoxicity of the chemotherapeutic agents. Consistently, cotreatment of AR42J cells with each of the chemotherapeutic agents in the presence of melatonin increased the population of apoptotic cells, elevated mitochondrial membrane depolarization, and augmented intracellular reactive oxygen species (ROS) production compared to treatment with each chemotherapeutic agent alone. These results provide evidence that in vitro melatonin enhances chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor AR42J cells and, therefore, melatonin may be potentially applied to pancreatic tumor treatment as a powerful synergistic agent in combination with chemotherapeutic drugs.

Venlafaxine is an approved antidepressant that is an inhibitor of both serotonin and norepinephrine transporters. Medical treatment with oral venlafaxine can be beneficial to depression due to reducing free radical production in the brain and medulla of depression-induced rats because oxidative stress may a play role in some depression. We investigated the effect of venlafaxine administration and experimental depression on lipid peroxidation and antioxidant levels in cortex brain, medulla and erythrocytes of rats. Thirty male wistar rats were used and were randomly divided into three groups. Venlafaxine (20 mg/kg) was orally supplemented to depression-induced rats constituting the first group for four week. Second group was depression-induced group although third group was used as control. Depressions in the first and second groups were induced on day zero of the study by chronic mild stress. Brain, medulla and erythrocytes samples were taken from all animals on day 28. Depression resulted in significant decrease in the glutathione peroxidase (GSH-Px) activity and vitamin C concentrations of cortex brain, glutathione (GSH) value of medulla although their levels were increased by venlafaxine administration to the animals of depression group. The lipid peroxidation levels in the three tissues and nitric oxide value in cortex brain elevated although their levels were decreased by venlafaxine administration. There were no significant changes in cortex brain vitamin A, erythrocytes vitamin C, GSH-Px and GSH, medulla vitamin A, GSH and GSH-Px values. In conclusion, cortex brain within the three tissues was most affected by oxidative stress although there was the beneficial effect of venlafaxine in the brain of depression-induced rats on investigated antioxidant defenses in the rat model. The treatment of depression by venlafaxine may also play a role in preventing oxidative stress.

Selenium is an essential chemopreventive antioxidant element to oxidative stress, although high concentrations of selenium induce toxic and oxidative effects on the human body. However, the mechanisms behind these effects remain elusive. We investigated toxic effects of different selenium concentrations in human promyelocytic leukemia HL-60 cells by evaluating Ca(2+) mobilization, cell viability and caspase-3 and -9 activities at different sample times. We found the toxic concentration and toxic time of H(2)O(2) as 100 microM: and 10 h on cell viability in the cells using four different concentrations of H(2)O(2) (1 microM: -1 mM: ) and six different incubation times (30 min, 1, 2, 5, 10, 24 h). Then, we found the therapeutic concentration of selenium to be 200 nM: by cells incubated in eight different concentrations of selenium (10 nM: -1 mM: ) for 1 h. We measured Ca(2+) release, cell viability and caspase-3 and -9 activities in cells incubated with high and low selenium concentrations at 30 min and 1, 2, 5, 10 and 24 h. Selenium (200 nM: ) elicited mild endoplasmic reticulum stress and mediated cell survival by modulating Ca(2+) release, the caspases and cell apoptosis, whereas selenium concentrations as high as 1 mM: induced severe endoplasmic reticulum stress and caused cell death by activating modulating Ca(2+) release, the caspases and cell apoptosis. In conclusion, these results explained the molecular mechanisms of the chemoprotective effect of different concentrations of selenium on oxidative stress-induced apoptosis.

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