Silencing of Mcl-1 overcomes resistance of melanoma cells against TRAIL-armed oncolytic adenovirus by enhancement of apoptosis

Arming of oncolytic viruses with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown as a viable approach to increase the antitumor efficacy in melanoma. However, melanoma cells may be partially or completely resistant to TRAIL or develop TRAIL resistance, thus counteracting the antitumor efficiency of TRAIL-armed oncolytic viruses. Recently, we found that TRAIL resistance in melanoma cells can be overcome by inhibition of antiapoptotic Bcl-2 protein myeloid cell leukemia 1 (Mcl-1). Here, we investigated whether the cytotoxicity of AdV-TRAIL, an oncolytic adenovirus, which expresses TRAIL after induction by doxycycline (Dox), can be improved in melanoma cells by silencing of Mcl-1. Two melanoma cell lines, the TRAIL-resistant MeWo and the TRAIL-sensitive Mel-HO were investigated. Treatment of both cell lines with AdV-TRAIL resulted in a decrease of cell viability, which was caused by an increase of apoptosis and necrosis. The proapoptotic effects were dependent on induction of TRAIL by Dox and were more pronounced in Mel-HO than in MeWo cells. SiRNA-mediated silencing of Mcl-1 resulted in a further significant decrease of cell viability and a further increase of apoptosis and necrosis in AdV-TRAIL-infected MeWo and Mel-HO cells. However, while in absolute terms, the effects were more pronounced in Mel-HO cells, in relative terms, they were stronger in MeWo cells. These results show that silencing of Mcl-1 represents a suitable approach to increase the cytotoxicity of a TRAIL-armed oncolytic adenovirus in melanoma cells.TU Berlin, Open-Access-Mittel – 202

European union enlargement to the East

As the Central and East European candidates for the next round of negotiation on joining the European Union were nominated, the debate on EU enlargement has reached a critical poin. Now the rhetoric of postulating European solidarity and emphasizing the openess of the Union for all European states is not enough anymore. Concrete steps must be taken both in the Union and the states applying for membership. The internal political, economic and societal reforms within the so called Visegrad states must be completed as well as the institutional framework of the European Union, including its patterns of decision-making. This article deals with question of reorganizing the administrative structure, e.g. to decentralize in order to anticipate the regional structure of the Union and the question of how the structure of the European agrarian policy should be reformed to make it fit for the competition with the new members

Die Region als politisch-kultureller Raum: Voraussetzungen für gesellschaftliche Regionalisierung in Polen, Ungarn und Rumänien

status: publishe