Chemopreventive potential of an ethyl acetate fraction from Curcuma longa is associated with upregulation of p57(kip2) and Rad9 in the PC-3M prostate cancer cell line.

BACKGROUND: Turmeric (Curcuma longa) has been shown to possess anti-inflammatory, antioxidant and antitumor properties. However, despite the progress in research with C. longa, there is still a big lacuna in the information on the active principles and their molecular targets. More particularly very little is known about the role of cell cycle genes p57(kip2) and Rad9 during chemoprevention by turmeric and its derivatives especially in prostate cancer cell lines. METHODS: Accordingly, in this study, we have examined the antitumor effect of several extracts of C. longa rhizomes by successive fractionation in clonogenic assays using highly metastatic PC-3M prostate cancer cell line. RESULTS: A mixture of isopropyl alcohol: acetone: water: chloroform: and methanol extract of C. longa showed significant bioactivity. Further partition of this extract showed that bioactivity resides in the dichloromethane soluble fraction. Column chromatography of this fraction showed presence of biological activity only in ethyl acetate eluted fraction. HPLC, UV-Vis and Mass spectra studies showed presence three curcuminoids in this fraction besides few unidentified components. CONCLUSIONS: From these observations it was concluded that the ethyl acetate fraction showed not only inhibition of colony forming ability of PC-3M cells but also up-regulated cell cycle genes p57(kip2) and Rad9 and further reduced the migration and invasive ability of prostate cancer cells.

Effect of melatonin on N-nitrosodiethylamine-induced hepatocarcinogenesis in rats with reference to biochemical circadian rhythms.

ABSTRACT Tumors and tumor-bearing hosts exhibit markedly altered circadian rhythms, which serve as markers in the early diagnosis and prognosis of cancer. Our study presents the effect of melatonin on circadian rhythms of lipid peroxides and antioxidants in N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis. The circadian rhythm characteristics (acrophase, amplitude, and mesor) of thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) were markedly altered in NDEA-treated rats. Melatonin administration caused a significant increase in the amplitude and mesor values of antioxidants and a significant decrease in the mesor values of TBARS. Further delays in acrophase in NDEA-treated rats were reversed by melatonin administration. In conclusion, melatonin may exert its chemopreventive effect by its role as an antioxidant as well as by altering the circadian rhythm characteristics.

Metabolic normalization of alpha-ketoglutarate against N-nitrosodiethylamine-induced hepatocarcinogenesis in rats.

Chemoprevention of cancer is one of the reliable approaches to control the incidence of cancer. In the present study, we investigated the chemopreventive role of alpha-ketoglutarate (alpha-KG) during N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis. The activities of serum aspartate and alanine transaminases were found to be significantly higher in NDEA + CCl(4)-treated animals when compared with control animals. Administration of alpha-KG restored the activities of transaminases to near normal range. The levels of lipid peroxides, thiobarbituric acid reactive substances were decreased in the liver tissue of NDEA + CCl(4)-treated animals when compared with control animals. alpha-KG reversed the lipid peroxide levels to near normal range. Levels of antioxidants, reduced glutathione and activities of its dependent enzymes, glutathione peroxidase and glutathione-S-transferase were found to be significantly higher in liver tissue of NDEA + CCl(4)-treated animals when compared with control animals. alpha-KG administration positively modulated the antioxidant levels to near normal range. In conclusion, it can be suggested that alpha-KG exerts chemopreventive role which may attributable to its ability to positively modulate the transaminase activities and oxidant-antioxidant imbalance during hepatocarcinogenesis.

Alpha-ketoglutarate modulates the circadian patterns of lipid peroxidation and antioxidant status during N-nitrosodiethylamine-induced hepatocarcinogenesis in rats.

The effect of alpha-ketoglutarate (alpha-KG) on circadian patterns of lipid peroxides and antioxidants in N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats has been studied. The circadian rhythm characteristics (acrophase, amplitude, and mesor) of thiobarbituric acid-reactive substances (TBARS), antioxidants, superoxide dismutase, catalase, glutathione peroxidase, and reduced glutathione were markedly altered in NDEA-treated rats. The delays in acrophase observed in NDEA-treated rats were brought back to near normal range by the administration of alpha-KG. An increase in mesor values of TBARS and a decrease in mesor values of antioxidants in NDEA-administered rats were reversed by alpha-KG administration. It can be concluded that alpha-KG exerts its chemopreventive effect by restoring antioxidants and their circadian rhythms.

Melatonin modulates the oxidant-antioxidant imbalance during N-nitrosodiethylamine induced hepatocarcinogenesis in rats.

PURPOSE: Melatonin, the principle hormone of pineal gland plays an important role in several biological processes. The effects of melatonin on hepatic marker enzymes [aspartate and alanine transaminases (AST and ALT)], lipid peroxides [thiobarbituric acid reactive substances (TBARS)] and antioxidants [reduced glutathione (GSH), glutathione peroxidase (GPx) and glutathione-S-transferase (GST)] during N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats were studied. METHODS: Male albino Wistar rats of body weight 150-170 g were divided into four groups of six animals each. Group I animals served as control, Group II animals received single intraperitoneal injection of NDEA at a dose of 200 mg/kg body weight followed by weekly subcutaneous injections of CCl4 at a dose of 3 mL/kg body weight. Group III animals were treated as in Group II and melatonin (5 mg/kg body weight) was administered intraperitoneally. Group IV animals received melatonin alone at the same dose as Group III animals. RESULTS: A significant increase in the activities of serum AST and ALT was observed in NDEA treated rats when compared with control animals. Melatonin administered rats showed a significant decrease in the activities of these enzymes when compared with NDEA treated animals. In the liver of NDEA-treated animals, decreased lipid peroxidation associated with enhanced antioxidant levels was observed. Administration of melatonin positively modulated these changes. CONCLUSION: Our results indicate that melatonin exerts chemopreventive effect by restoring the activities of hepatic marker enzymes and reversing the oxidant-antioxidant imbalance during NDEA-induced hepatocarcinogenesis.

Effects of ornithine alpha-ketoglutarate on circulatory antioxidants and lipid peroxidation products in ammonium acetate treated rats.

The effects of ornithine alpha-ketoglutarate (OKG) on ammonium acetate induced hepatotoxicity were studied biochemically in rats. The levels of urea, nonprotein nitrogen, and thiobarbituric acid reactive substances were significantly increased in ammonium acetate treated rats; these levels were significantly decreased in rats treated with ammonium acetate and OKG. Similar patterns of alterations were observed in the levels of free fatty acids, triglycerides, and phospholipids. Furthermore, nonenzymatic antioxidants (vitamins C and E) were significantly decreased in ammonium acetate treated rats, when compared with control rats, and increased in OKG and ammonium acetate treated rats. The biochemical alterations during OKG treatment could be (1) by detoxifying excess ammonia; (2) by participating in nonenzymatic oxidative decarboxylation in the hydrogen peroxide decomposition process, and (3) by enhancing the proper metabolism of fats which could suppress oxygen radical generation and thus prevent the lipid peroxidative damages in rats.

Ornithine alpha-ketoglutarate modulates the levels of antioxidants and lipid peroxidation products in ammonium acetate treated rats.

The effects of ornithine alpha-ketoglutarate (OKG) on ammonium acetate induced hepatotoxicity were studied in experimental rats. The levels of urea, non-protein nitrogen and thiobarbituric acid reactive substances were significantly increased in ammonium acetate treated rats; but these levels were significantly decreased in ammonium acetate-OKG treated rats. Similar patterns were observed in the levels of free fatty acids, triglycerides and phospholipids. Furthermore, non-enzymatic (reduced glutathione) and enzymatic (glutathione peroxidase, superoxide dismutase and catalase) antioxidants were significantly decreased in ammonium acetate treated rats, when compared with control and were significantly increased in ammonium acetate-OKG treated rats compared to ammonium acetate treatment alone.

Protective influences of alpha-ketoglutarate on lipid peroxidation and antioxidant status in ammonium acetate treated rats.

The effects of alpha-ketoglutarate on ammonium acetate induced hyperammonemia were studied biochemically in experimental rats. The levels of circulatory, non-protein nitrogen, serum transaminases and thiobarbituric acid reactive substances were significantly increased in ammonium acetate treated rats. These levels were significantly decreased in alpha-ketoglutarate and ammonium acetate treated rats. Similar patterns of alterations were observed in the levels of free fatty acids, triglycerides, phopholipids and cholesterol inbetween various groups. Further non-enzymatic (vitamins C and E) and enzymatic (superoxide dismutase and catalase) antioxidants were significantly decreased in ammonium acetate treated rats; and were significantly increased in alpha-ketoglutarate and ammonium acetate treated rats. The biochemical alterations during alpha-ketoglutarate treatment could be due to (i) the detoxification of excess ammonia, (ii) by participating in the non-enzymatic oxidative decarboxylation in the hydrogen peroxide decomposition process and (iii) by enhancing the proper metabolism of fats which could suppress oxygen radicals generation and thus prevent the lipid peroxidative damages in rats.