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An acidic environment and hypoxia within the tumour are hallmarks of cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common in colon cancer. Numerous Akt‐targeted therapies are being developed, the activity of Akt‐inhibitors is, however, strongly pH‐dependent. Combination therapy thus represents an opportunity to increase their efficacy. In this study, the cytotoxicity of the Akt inhibitor perifosine and the Bcl‐2/Bcl‐xL inhibitor ABT‐737 was tested in colon cancer HT‐29 and HCT‐116 cells cultured in monolayer or in the form of spheroids. The efficacy of single drugs and their combination was analysed in different tumour‐specific environments including acidosis and hypoxia using a series of viability assays. Changes in protein content and distribution were determined by immunoblotting and a "peeling analysis" of immunohistochemical signals. While the cytotoxicity of single agents was influenced by the tumour‐specific microenvironment, perifosine and ABT‐737 in combination synergistically induced apoptosis in cells cultured in both 2D and 3D independently on pH and oxygen level. Thus, the combined therapy of perifosine and ABT‐737 could be considered as a potential treatment strategy for colon cancer. [ABSTRACT FROM AUTHOR]

Abstract Background The c-Myb transcription factor is essential for the maintenance of stem-progenitor cells in bone marrow, colon epithelia, and neurogenic niches. c-Myb malfunction contributes to several types of malignancies including breast cancer. However, the function of c-Myb in the metastatic spread of breast tumors remains unexplored. In this study, we report a novel role of c-Myb in the control of specific proteases that regulate the matrix-dependent invasion of breast cancer cells. Results Ectopically expressed c-Myb enhanced migration and ability of human MDA-MB-231 and mouse 4T1 mammary cancer cells to invade Matrigel but not the collagen I matrix in vitro. c-Myb strongly increased the expression/activity of cathepsin D and matrix metalloproteinase (MMP) 9 and significantly downregulated MMP1. The gene coding for cathepsin D was suggested as the c-Myb-responsive gene and downstream effector of the migration-promoting function of c-Myb. Finally, we demonstrated that c-Myb delayed the growth of mammary tumors in BALB/c mice and affected the metastatic potential of breast cancer cells in an organ-specific manner. Conclusions This study identified c-Myb as a matrix-dependent regulator of invasive behavior of breast cancer cells.

Abstract Background Bacteriocin production is an important characteristic of E. coli strains of human origin. To date, 26 colicin and 9 microcin types have been analyzed on a molecular level allowing molecular detection of the corresponding genes. The production incidence of 29 bacteriocin types and E. coli phylogroups were tested in a set of 361 E. coli strains isolated from human urinary tract infections (UTI) and in 411 control strains isolated from feces of patients without bacterial gut infection. Results Production of 17 and 20 individual bacteriocin types was found in the UTI and control strains, respectively. Microcin H47 encoding determinants were found more often among UTI strains compared to controls (37.9% and 27.0% respectively, p = 0.02) and strains producing microcin H47 belonged predominantly to phylogroup B2 when compared to other bacteriocin producers (67.4% and 36.7%, respectively; p < 0.0001). Producers of 3 or more identified bacteriocin types were more common in the UTI group (20.0% compared to 12.4% in controls, p = 0.03). In the UTI strains, there was a markedly higher number of those producing colicin E1 compared to controls (22.1% to 10.2%, respectively, p = 0.0008). Moreover, colicin E1 production was more common in the UTI bacteriocinogenic strains with multi-producer capabilities. As shown by Southern blotting, pColE1 DNA was not recognized by the ColIa probe and vice versa suggesting that pColE1 was independently associated with pColIa in UTI strains. Conclusion E. coli strains isolated from human urinary tract infections showed increased incidence of microcin H47 and colicin E1 production, respectively. Moreover, colicin E1 itself appears to be a potentially important virulence factor of certain uropathogenic E. coli strains.