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      • Early Activation of Apoptosis and Caspase-independent Cell Death Plays an Important Role in Mediating the Cytotoxic and Genotoxic Effects of WP 631 in Ovarian Cancer Cells

        Gajek, Arkadiusz,Denel-Bobrowska, Marta,Rogalska, Aneta,Bukowska, Barbara,Maszewski, Janusz,Marczak, Agnieszka Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.18

        The purpose of this study was to provide a detailed explanation of the mechanism of bisanthracycline, WP 631 in comparison to doxorubicin (DOX), a first generation anthracycline, currently the most widely used pharmaceutical in clinical oncology. Experiments were performed in SKOV-3 ovarian cancer cells which are otherwise resistant to standard drugs such as cis-platinum and adriamycin. As attention was focused on the ability of WP 631 to induce apoptosis, this was examined using a double staining method with Annexin V and propidium iodide probes, with measurement of the level of intracellular calcium ions and cytosolic cytochrome c. The western blotting technique was performed to confirm PARP cleavage. We also investigated the involvement of caspase activation and DNA degradation (comet assay and immunocytochemical detection of phosphorylated H2AX histones) in the development of apoptotic events. WP 631 demonstrated significantly higher effectiveness as a pro-apoptotic drug than DOX. This was evident in the higher levels of markers of apoptosis, such as the externalization of phosphatidylserine and the elevated level of cytochrome c. An extension of incubation time led to an increase in intracellular calcium levels after treatment with DOX. Lower changes in the calcium content were associated with the influence of WP 631. DOX led to the activation of all tested caspases, 8, 9 and 3, whereas WP 631 only induced an increase in caspase 8 activity after 24h of treatment and consequently led to the cleavage of PARP. The lack of active caspase 3 had no outcome on the single and double-stranded DNA breaks. The obtained results show that WP 631 was considerably more genotoxic towards the investigated cell line than DOX. This effect was especially visible after longer times of incubation. The above detailed studies indicate that WP 631 generates early apoptosis and cell death independent of caspase-3, detected at relatively late time points. The observed differences in the mechanisms of the action of WP631 and DOX suggest that this bisanthracycline can be an effective alternative in ovarian cancer treatment.

      • Electric modulation of conduction in multiferroic Ca-doped BiFeO<sub>3</sub> films

        Yang, C.-H.,Seidel, J.,Kim, S. Y.,Rossen, P. B.,Yu, P.,Gajek, M.,Chu, Y. H.,Martin, L. W.,Holcomb, M. B.,He, Q.,Maksymovych, P.,Balke, N.,Kalinin, S. V.,Baddorf, A. P.,Basu, S. R.,Scullin, M. L.,Rames Nature Publishing Group 2009 Nature materials Vol.8 No.6

        Many interesting materials phenomena such as the emergence of high-Tc superconductivity in the cuprates and colossal magnetoresistance in the manganites arise out of a doping-driven competition between energetically similar ground states. Doped multiferroics present a tantalizing evolution of this generic concept of phase competition. Here, we present the observation of an electronic conductor–insulator transition by control of band-filling in the model antiferromagnetic ferroelectric BiFeO<SUB>3</SUB> through Ca doping. Application of electric field enables us to control and manipulate this electronic transition to the extent that a p–n junction can be created, erased and inverted in this material. A ‘dome-like’ feature in the doping dependence of the ferroelectric transition is observed around a Ca concentration of ∼1/8, where a new pseudo-tetragonal phase appears and the electric modulation of conduction is optimized. Possible mechanisms for the observed effects are discussed on the basis of the interplay of ionic and electronic conduction. This observation opens the door to merging magnetoelectrics and magnetoelectronics at room temperature by combining electronic conduction with electric and magnetic degrees of freedom already present in the multiferroic BiFeO<SUB>3</SUB>.

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