Cathepsin L in metastatic bone disease: therapeutic implications

Cathepsin L is a lysosomal cysteine proteinase primarily devoted to the metabolic turnover of intracellular proteins. However, accumulating evidence suggests this endopeptidase may be also implicated in the regulation of other important biological functions including bone resorption in normal and pathological conditions. These findings support the concept that cathepsin L, in concert with other proteolytic enzymes involved in bone remodelling processes, may contribute to facilitate bone metastasis formation. In support of this hypothesis, recent studies indicate that cathepsin L may foster this process by triggering multiple mechanisms which, in part, differ from those of the major cysteine proteinase of osteoclast, namely cathepsin K. Therefore, cathepsin L may be regarded as an additional target in the treatment of patients with metastatic bone disease. This review discusses the clinical and therapeutic implications related to these findings

Follistatin as potential therapeutic target in prostate cancer

Follistatin is a single-chain glycosylated protein whose primary function consists in binding and neutralizing some members of the transforming growth factor-β superfamily such as activin and bone morphogenic proteins. Emerging evidence indicates that this molecule may also play a role in the malignant progression of several human tumors including prostate cancer. In particular, recent findings suggest that, in this tumor, follistatin may also contribute to the formation of bone metastasis through multiple mechanisms, some of which are not related to its specific activin or bone morphogenic proteins’ inhibitory activity. This review provides insight into the most recent advances in understanding the role of follistatin in the prostate cancer progression and discusses the clinical and therapeutic implications related to these findings

Anti-proliferative and pro-apoptotic activities of hydroxytyrosol on different tumour cells: the role of extracellular production of hydrogen peroxide

Several recently published data suggest that the anti-proliferative and pro-apoptotic properties of hydroxytyrosol [3,4-dihydroxyphenyl ethanol (3,4-DHPEA)] on HL60 cells may be mediated by the accumulation of hydrogen peroxide (H2O2) in the culture medium. The aim of this study was to clarify the role played by H2O2 in the chemopreventive activities of 3,4-DHPEA on breast (MDA and MCF-7), prostate (LNCap and PC3) and colon (SW480 and HCT116) cancer cell lines and to investigate the effects of cell culture medium components and the possible mechanisms at the basis of the H2O2-producing properties of 3,4-DHPEA. The proliferation was measured by the MTT assay and the apoptosis by both fluorescence microscopy and flow cytometry. The concentration of H2O2 in the culture medium was measured by the ferrous ion oxidation-xylenol orange method. It was found that the H2O2-inducing ability of 3,4-DHPEA is completely prevented by pyruvate and that the exposure of cells to conditions not supporting the H2O2 accumulation (addition of either catalase or pyruvate to the culture medium) inhibited the anti-proliferative effect of 3,4-DHPEA. Accordingly, the sensitivity of the different cell lines to the anti-proliferative effect of 3,4-DHPEA was inversely correlated with their ability to remove H2O2 from the culture medium. With regard to the mechanism by which 3,4-DHPEA causes the H2O2 accumulation, it was found that superoxide dismutase increased the H2O2 production while tyrosinase, slightly acidic pH (6,8) and absence of oxygen (O-2) completely prevented this activity. In addition, different transition metal-chelating compounds did not modify the H2O2-producing activity of 3,4-DHPEA. The pro-oxidant activity of 3,4-DHPEA deeply influences its 'in vitro' chemopreventive activities. The main initiation step in the H2O2-producing activity is the auto-oxidation of 3,4-DHPEA by O-2 with the formation of the semiquinone, superoxide ions (O-2 (-)) and 2H(+

Antiproliferative and proapoptotic activities of hydroxytyrosol derivatives on human promyelocytic leukemia cell lines

Purpose Hydroxytyrosol (3,4-DHPEA) derivatives (disulfide, thioacetate and thiohydroxytyrosol) were synthesized in order to test in vitro if the combination of catechol moiety of 3,4-DHPEA and sulfur containing functions results in an improvement of the pro-apoptotic and anti-proliferative activities shown by 3,4-DHPEA. The involvement of H2O2 production in the cell culture medium has been studied. Methods The effects of thiohydroxytyrosol derivatives and 3,4-DHPEA on cell proliferation, apotosis and cell cycle of HL60 and its MDR variant HL60R were assessed by the Trypan Blue exclusion test, by fluorescence microscopy or by flow cytometry respectively. H2O2 concentrations in the culture medium was measured by the ferrous ion oxidation-xylenol orange method. Results We found that: i) all synthesized compounds were able to inhibit the proliferation inducing apoptosis on both cell lines HL60 and HL60R; ii) all thiohydroxytyrosol derivatives were more effective than 3,4-DHPEA in inducing apoptosis on HL60R; iii) differently from 3,4-DHPEA, the proapoptotic activities of thiohydroxytyrosol derivatives were not dependent upon the release of H2O2 in the culture medium; iv) the hydroxytyrosol disulfide was the most active pro-apoptotic and anti-proliferative compound on both HL60 and HL60R cells. Conclusions The combination of cathecol moiety and sulfur functions resulted in an improvement of 3,4-DHPEA proapoptotic activity which was particularly evident on HL60R cells suggesting that these compounds could be potentially used in cancer therapy and could be able to reverse the resistance toward the most common anticancer drugs