Jirina Hofmanova

Docosahexaenoic fatty acid (DHA) in the regulation of colon cell growth and cell death: a review.

BACKGROUND Experimental, epidemiological and clinical data substantiate the beneficial role of n-3 polyunsaturated fatty acids (PUFAs) in preventing inflammation and cancer of the colon. This review covers the unsaturated docosahexaenoic fatty acid (DHA), describes some of its important cellular and molecular mechanisms, its interaction with another dietary lipid, butyrate and with endogenous apoptotic regulators of the tumour necrosis factor (TNF) family. We also discuss the clinical impact of this knowledge and the use of these lipids in colon cancer prevention and treatment. RESULTS From the literature, DHA has been shown to suppress the growth, induce apoptosis in colon cancer cells in vitro and decrease the incidence and growth of experimental tumours in vivo. Based on these data and our own experimental results, we describe and discuss the possible mechanisms of DHA anticancer effects at various levels of cell organization. We show that DHA can sensitize colon cancer cells to other chemotherapeutic/chemopreventive agents and affect the action of physiological apoptotic regulators of the TNF family. CONCLUSION Use of n-3 PUFAs could be a relatively non-toxic form of supportive therapy for improving colon cancer treatment and slowing down or preventing its recurrence. However, it is necessary to use them with caution, based on solid scientific evidence of their mechanisms of action from the molecular to the cellular and organism levels.

5-Lipoxygenase inhibitors potentiate effects of TGF-beta 1 on the differentiation of human leukemia HL-60 cells.

It was clearly demonstrated that two structurally different inhibitors of 5‐lipoxygenase (5‐LPO) metabolism (leukotriene synthesis), i.e. MK‐886 and esculetin, when combined with transforming growth factor‐β1 (TGF‐β1), significantly enhanced the differentiation but did not change proliferation (i.e. cell number and cell cycle parameters) of human leukemia HL‐60 cells in vitro. Although cell morphology and measurement of cell surface antigens (CD11b, CD14, and CD66b) after 48 h of combined treatment with MK‐886 and TGF‐β1 suggested a shift of the HL‐60 cell population into more differentiated stages of myelopoiesis, cells with a fully mature phenotype were not observed. The effects on differentiation were better distinguished in the functional parameters of differentiation, i.e. oxidative burst of cells as detected by chemiluminescence and the nitroblue tetrazolium reduction test. Detailed statistical analysis of these data proved a significant synergistic interaction between TGF‐β1 and inhibitors of 5‐LPO metabolism. The differentiation effects of TGF‐β1 alone and especially of its combination with MK‐886 were most pronounced when the cells were pretreated with dimethyl sulfoxide or all‐trans‐retinoic acid. The results imply that either the lack of 5‐LPO metabolites or a certain type of mis‐balance in arachidonic acid metabolism can modulate the TGF‐β1 effect on myeloid differentiation. J. Leukoc. Biol. 62: 240–248; 1997.

Regulation of the metabolism of polyunsaturated Fatty acids and butyrate in colon cancer cells.

Experimental and epidemiological evidence supports the idea that dietary fat and fiber influence colon carcinogenesis. Particularly, their components, n-3 polyunsaturated fatty acids (PUFAs) and butyrate, have been proven to exhibit beneficial effects on colon epithelial cell metabolism, signaling, and kinetics, thus preventing colon inflammation and cancer. Moreover, these effects may be strengthened by PUFA and butyrate combination. It appears that administration of these compounds might be a relatively nontoxic form of supportive therapy improving cancer treatment outcomes and slowing down or preventing recurrence of certain types of cancer. However, their efficient application has to be based on solid scientific evidence of their mechanisms of action from the molecular and cellular to the organismal level. In this review, we emphasize the role of lipids and their metabolism during tumor development, describe some important mechanisms considering cellular and molecular levels of PUFA and butyrate action in colon epithelial cells, and particularly focus on the interaction of their metabolism and the signaling pathways with respect to the differences in response of normal and cancer colon cells.