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Application of platinum-based chemotherapy that is currently used for treatment of malignant tumors is accompanied by several problems such as acquired resistance of cancer cells and negative side effects on normal tissues. Therefore, there is a need for introduction and testing of new drugs with more efficient and selective action. Platinum (IV) adamantylamine ligand-containing complex LA-12 is able to induce death in colon cancer cells and sensitize them to other apoptosis-inducing agents, which results in more effective cancer cell elimination. We investigated whether LA-12 can modulate the response of colon cancer cells to TRAIL (tumor necrosis factor-related apoptosis inducing ligand), a unique cytokine that selectively promotes apoptosis in tumor but not in normal cells. We report that LA-12 mediates effective sensitization of colon cancer cells to apoptosis induced by TRAIL. A functional role of TRAIL DR5 in LA-12-mediated potentiation of TRAIL-induced apoptosis was verified previously by us using specific siRNA. Here we show that the cytotoxic effects of LA-12+TRAIL are p53-independent, as similar cytotoxic response to this combination can be observed in model cell lines with wild type, mutant or lacking p53 protein. During colon cancer development sequential accumulation of characteristic mutations occurs. Biological behavior of cells may differ in diverse stages of the disease, as well as their response to therapy. Combination of LA-12 and TRAIL effectively promoted apoptosis of colon cancer cells derived from carcinoma (HCT116, SW480) and metastasis (SW620). Interestingly, it has also been shown by us to exert its cytotoxicity in human colon adenoma cells (AA/C1). In contrast, normal human colon epithelial cell line (NCM460) was not susceptible to LA-12 and TRAIL when applied in concentrations harmful to cancer cells. Our results suggest that combination of LA-12 and TRAIL may be a promising strategy for anticancer treatment even in tumors with non-functional p53 and in various stages of colon cancer development. [ABSTRACT FROM AUTHOR]

The disturbance of imbalance between proliferation, differentiation and apoptosis in the intestinal epithelium plays important role in colorectal carcinogenesis. The development of this disease can be significantly influenced by dietary lipids, especially by specific types of fatty acids. These compounds are important modulators of many aspects of intestinal epithelial cell behaviour. Their role in inflammation and carcinogenesis is assumed because of their ability to inhibit cell proliferation and induce differentiation and/or apoptosis. Thus, we investigated the response of human epithelial cell lines derived from fetal colon (FHC) and colon adenocarcinoma (HT-29) to essential ω-3 polyunsaturated docosahexaenoic acid (DHA), sodium butyrate (NaBt), short chain fatty acid produced by microbial fermentation of fibre in the colon, and their combination. The aim of our study was: a) to explain some mechanisms of combined NaBt and DHA action b) to determine the role of PI3K/Akt signaling pathway in the effects of studied fatty acids. Results obtained by flow cytometry, fluorimetry analysis and expression of specific proteins (western blot) showed that combination of these compounds increases their antiproliferative as well as apoptotic effects and modulates differentiation depending on cell line. These effects were associated with membrane lipid structure changes, increased lipid droplet accumulation, reduced mitochondrial membrane potential, increased production of reactive oxygen species and changes in the expression or activity of some regulatory molecules connected with apoptosis (caspases, Bax, Bak, Bid, Mcl-1, survivin, XIAP) and lipid metabolism such as fatty acid synthase, caveolin-1 and peroxisome proliferator-activated receptor (PPAR) γ. After Akt 1/2 inhibitor application we detected significant changes in cytokinetics and lipid metabolism suggesting the involvement of the PI3K/Akt pathway in the effects of fatty acids. [ABSTRACT FROM AUTHOR]

Cancer cells can often be characterized by resistance to therapeutic drugs due to dysfunction of various intracellular signaling pathways, including those involved in regulation of lipid metabolism. Ceramides are the basic units of the sphingolipids and can play role in modulation of the cytotoxic action of various anticancer agents. Docosahexaenoic acid (DHA), n-3 polyunsaturated fatty acid, is an important component of cellular membranes, able to modulate processes such as proliferation, differentiation or apoptosis in various cancer cell types. It is documented that DHA and ceramides can modulate processes that are important for induction of apoptosis in cancer cells. We investigated the sensitizing effect of DHA on apoptosis triggered by TRAIL (TNF-related apoptosis inducing ligand) in human epithelial cell line derived from colon cancer metastasis, and its association with ceramide metabolism. TRAIL is a cytokine known for its ability to selectively induce apoptosis in cancer cells, but not in most normal cells. However, many cancer cells including colon are still resistant to cytotoxic effects of TRAIL. In our colon cancer cell model we showed that DHAmediated potentiation of TRAIL-induced apoptosis was associated with enhanced activation of caspases, cleavage of their substrates, and stimulation of mitochondrial pathway. These events were accompanied by significant changes of amount of selected lipid classes. Cellular lipid analysis (HPLC-MS-MS) showed that DHA increased amount of so-called proapoptotic ceramide classes (16:0). Moreover, DHA decreased amount of lipid classes (24:1) which were demonstrated to play a role in cancer cell resistence to TRAIL. [ABSTRACT FROM AUTHOR]