Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitro and in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA-MB-231 cells in correlation with reduced activation of the survival pathway NFκB, as a consequence of diminished ΙκΒ and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NFκB activity and transcriptional downregulation of AP-1. NFκB/p65 silencing is sufficient to downregulate cjun and MMP expression. Reduced NFκB/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NFκB/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible.

BackgroundCurcumin induces apoptosis in many cancer cells and it reduces xenograft growth and the formation of lung metastases in nude mice. Moreover, the plant derived polyphenol has been reported to be able to overcome drug resistance to classical chemotherapy. These features render the drug a promising candidate for tumor therapy especially for cancers known for their high rates concerning therapy resistance like melanoma.ResultsWe show here that the melanoma cell line M14 is resistant to Curcumin induced apoptosis, which correlates with the absence of any effect on NFκB signaling. We show that CXCL1 a chemokine that is down regulated in breast cancer cells by Curcumin in an NFκB dependant manner is expressed at variable levels in human melanomas. Yet in M14 cells, CXCL1 expression did not change upon Curcumin treatment. Following the hypothesis that Curcumin is rapidly removed from the resistant cells, we analyzed expression of known multi drug resistance genes and cellular transporters in M14 melanoma cells and in the Curcumin sensitive breast cancer cell line MDA-MB-231. ATP-binding cassette transporter ABCA1, a gene involved in the cellular lipid removal pathway is over-expressed in resistant M14 melanoma as compared to the sensitive MDA-MB-231 breast cancer cells. Gene silencing of ABCA1 by siRNA sensitizes M14 cells to the apoptotic effect of Curcumin most likely as a result of reduced basal levels of active NFκB. Moreover, ABCA1 silencing alone also induces apoptosis and reduces p65 expression.ConclusionResistance to Curcumin thus follows classical pathways and ABCA1 expression should be considered as response marker.

Matrix dissolution is a crucial step during tumor progression that converts a premalignant cell to an overtly malignant one. Main players in this step are the various matrix metalloproteinases (MMPs), which differ in substrate specificity and tissue distribution, and thereby also differ in presence and function during various stages of initial and systemic tumor spread. Accordingly, the inhibition of MMP synthesis and/or activity represents novel potential therapeutic strategies for the treatment of cancer patients. Considerable work has already been carried out on synthetic inhibitors of MMP activity, but with little or even adverse effects in recent clinical studies. The reasons may be inappropriate patient populations in too advanced tumor stages, or inappropriate enzymes as targets for inhibition. Upregulation of endogenous tissue inhibitors of MMP (TIMPs) also provided ambiguous results, since TIMPs possess biologic functions in addition to MMP inhibition, for example, TIMP-2 is a main player in the MMP-2 activation cascade. This may explain, at least in part, the adverse effects of TIMP application/upregulation. Other strategies have been sought in order to overcome these problems. These include the downregulation of MMP transcription by cytokines. However, the effects of cytokines (other than MMP inhibition) may also limit the use of this approach. Finally, empiric evidence for control and modulation of MMP transcription and/or activation by several naturally occurring substances, such as flavonoids, green tea polyphenols and curcumin, represent novel options for the control of MMP activity even in early tumor stages. Additionally, these substances have little or no toxic side effects and good bioavailability, and therefore their continuing analysis provides intriguing insight into tumor pathophysiology and possibly new therapeutic options.

Discovery of naturally occurring boron complexes with organic compounds containing hydroxyl groups, sugars, and polysaccharides, adenosine-5-phosphate, pyridoxine, riboflavin, dehydroascorbic acid, and pyridine nucleotides led to the reassessment of the biochemical role of boron. Boron's anti-inflammatory actions were claimed but not yet demonstrated. This study investigated the effects of calcium fructoborate (CF) on the human polymorphonuclear neutrophils (PMN) that play a central role in the inflammatory response. Our results demonstrated that CF exposure induced a dose-dependent decrease in cell viability. Treatment of PMN cells, for 24 h, with 22,500 microM CF led to a decrease in cell viability by 61.1%, an inhibition of respiratory burst by 92.9% in the case of fMLP-stimulated cells, a diminution of intracellular level of superoxide anion with 59.3%, and a stimulation of superoxide dismutase activity by 72% in unstimulated PMN cells. Altogether, these results suggest the antioxidant and anti-inflammatory properties of CF.