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Je hanba, že se někdo dovede namáhat po mnoho let, aby se stal dobrým lékařem, obhájcem, učitelem nebo geometrem, a přitom není ochoten namáhat se příslušně dlouhý čas, aby se stal dobrým člověkem.

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Cisplatin-resistant prostate cancer model

Cis-diamminedichloroplatinum or cisplatin is an inorganic compound that is widely used as a therapy of cancers. The biochemical mechanisms of cisplatin cytotoxicity involve the binding of the drug to DNA and non-DNA targets and the subsequent induction of cell death through apoptosis, necrosis, or both [1]. It follows that altered expression of regulatory proteins involved in signal transduction pathways that control the apoptosis, necrosis or cell defense mechanisms (Fig. 1) can additionally make certain types of cancer rather insensitive to cytotoxic effects of cisplatin [2,3], which is, among others, case of later stages of prostate cancer. Cellular mechanisms of resistance to cisplatin are multifactorial and result in severe limitations in clinical use [4,5,6]. Therefore, cisplatin resistance model was formed from prostatic cell lines PNT1A, PC-3, and 22Rv1 in this study. The PC-3 cell line was derived from a metastasis of a high grade androgen irresponsive prostate cancer. Cisplatin resistance is presumed in these cells due non-functional p53 [7]. Tumor suppressor protein p53 plays a critical role in regulating cell cycle arrest, DNA repair and apoptosis [8]. Accordingly, tumor cells lacking functional p53 were found more resistant to cisplatin than cells that contained functional p53 and the resistant cell lines were sensitized to cisplatin upon reconstitution with wild-type p53 [9]. Among other alterations in cellular response to the cisplatin, oxidative stress might be triggered [10,11]. In previous studies, the central role of mitochondria damage in the cisplatin-induced toxicity was demonstrated and it is suggested that it probably occurs due to augmented ROS (reactive oxygen species) generation, with consequent impairment of mitochondrial function and structure, depletion of the key components of the mitochondrial antioxidant defence system (GSH and NADPH) and cellular death by apoptosis [12,13]. Therefore, understanding the expression of anti- and pro-apoptotic proteins and their relationship to redox system in the cell upon cisplatin treatment will provide valuable insight into the development of cisplatin resistance [11]. Therefore, the expression of key apoptosis signalling genes (Bax and Bcl-2) and cell defensive thiol-containing molecule metallothionein (MT) were investigated in this study in different cisplatin concentrations and length of treatment. Additionally, main antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) and antioxidant capacity with respect to the cisplatin treatment were analysed in this study. MT binds rapidly to platinum and thus sequester cisplatin and remove it from the cells. This binding has primarily been associated with the development of resistance [9]. However, there is still a level of inconsistence between studies. In some cases, the levels of MT are higher in cisplatin-resistant cells, but in other cases, the MT levels are unaffected [2]. In sum, differences in antioxidant system, apoptotic mechanism and in cell cycle between prostatic cell lines could partially elucidate the development of cisplatin resistance. Thus, the aim of this study was i) to identify the most characteristic parameter for particular cell line and/or particular cisplatin treatment using general regression model and ii) to assess, whether it is possible to use measured parameters as markers of cisplatin resistance.

Podpořeno projekty: CYTORES GA ČR

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