MMP-2, MMP-9 and their inhibitors TIMP-2 and TIMP-1 production by human monocytes in vitro in the presence of different forms of hydroxyapatite particles.

DOI : 10.1016/j.biomaterials.2003.09.034After calcium-phosphates biomaterials based implantation like hydroxyapatite (HA) coating, particles are released in the periprosthetic tissues. Wear-debris induced fibrous membranes contain macrophage subsets that can produce metalloproteinases (MMPs), which are considered to be key enzymes in extra-cellular matrix turnover. Tissue inhibitors of metalloproteinases (TIMPs) are important regulator of MMPs activity. Interleukin-1 mainly produced by monocytes can also regulate MMPs production. In the present work, we have evaluated the effect of HA particles characteristics (size, shape and sintering temperature) on the MMP-2, -9 and their respective inhibitors TIMP-2, -1 production. Our results demonstrate that sintering temperature (that modify crystal size and surface area) have little effect on MMPs and TIMPs production. Non-phagocytable particles induced more MMP-9, although phagocytable particles induced more IL-1β release. The shape of the particles was the most important factor since needle-shaped particles induced the most significant up-regulated expression of MMPs and IL-1β

Activité antiinvasive des anthracyclines antitumorales : effets de l'aclacinomycine sur les propriétés migratoires et invasives des cellules de fibrosarcome humain HT-1080

@Nous avons étudié les effets des anthracyclines antitumorales, en particulier l'aclacinomycine, sur les capacités migratoires et invasives de cellules à fort pouvoir invasif, la lignée de fibrosarcome humain HT-1080. Nous avons démontré que l'aclacinomycine et dans une moindre mesure la doxorubicine inhibent la migration et l'invasion des cellules HT-1080 à des concentrations n'affectant pas la croissance cellulaire. Cette inhibition des propriétés invasives n'implique pas des mécanismes de dégradation protéolytique de la matrice extracellulaire. Par contre, elle met en jeu des modifications au niveau des protéines du cytosquelette et des plaques d'adhésion focale. Nous avons observé un défaut de polarisation cellulaire, une altération des lamellipodes et de son réseau d'actine . En particulier, l'effet antiinvasif est associé à une diminution de l'expression des intégrines b1 et de leur état d'affinité. On note également une diminution de l'expression des tyrosines kinases FAK et Src et l'altération de leur état de phosphorylation. L'ensemble des résultats suggère que l'aclacinomycine pourrait être utilisée en clinique humaine à d'autres fins que son pouvoir cytotoxique.@Aclacinomycin (Aclarubicinâ) is a trisaccharide anthracycline anticancer drug active against a wide variety of solid tumors and haematological malignancies. We have evaluated its antimigrative and antiinvasive properties in a Boyden chamber with or without Matrigel and in wound repair assays. Aclacinomycin was demonstrated to inhibit HT-1080 cell migration and invasion while being more potent than the classical anthracycline doxorubicin. This decrease occurred in a dose-dependent manner and without affecting cell proliferation. Importantly, the antiinvasive effect was not associated to a modification in the production of the matrix-degrading enzymes MMP-2 and MMP-9 but rather to changes in cytoskeletal and focal contact formation. Indeed, the drug reduces cell polarity, impairs the actin-mediated membrane ruffling at the leading edge and decreases b1 integrin expression and activation. Dramatic alterations in the distribution of vinculin and in the expression and phosphorylation state of both FAK and Src kinases were also detected. As a conclusion, these data suggest a novel application for this chemotherapeutic agent due to its ability to reduce tumor cell invasion. Combination of aclacinomycin with MMP inhibitors could have therapeutic potential in preventing tumor metastasis.REIMS-BU Santé (514542104) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Assessment of the antiinvasive potential of the anthracycline aclacinomycin (Aclarubicin) in a human fibrosarcoma cell line.

Aclacinomycin (Aclarubicin) is a trisaccharide anthracycline anticancer drug active against a wide variety of solid tumors and haematological malignancies. We have evaluated its antimigrative and antiinvasive properties in a Boyden chamber with or without Matrigel and in wound repair assays. Aclacinomycin was demonstrated to inhibit HT-1080 cell migration and invasion while being more potent than the classical anthracycline doxorubicin. This decrease occurred in a dose-dependent manner and without affecting cell proliferation. Importantly, the antiinvasive effect was not associated to a modification in the production of the matrix-degrading enzymes MMP-2 and MMP-9 but rather to changes in cytoskeletal and focal contact formation. Indeed, the drug reduces cell polarity, impairs the actin-mediated membrane ruffling at the leading edge and decreases beta1 integrin expression and activation. Dramatic alterations in the distribution of vinculin and in the expression and phosphorylation state of both FAK and Src kinases were also detected. As a conclusion, these data suggest a novel application for this chemotherapeutic agent due to its ability to reduce tumor cell invasion. Combination of aclacinomycin with MMP inhibitors could have therapeutic potential in preventing tumor metastasis