Abstract
Prostate cancer (PCa) is the most common malignancy in men and represents the second leading cause of cancer deaths in Western countries. PCa is initially androgen-dependent, however, this tumor inevitably progresses as castration-resistant prostate cancer (CRPC), which represents the most aggressive phase of the pathology. In this work, in two CRPC cell lines (DU145 and PC3), we studied the in vitro inhibitory properties of the tryptophan-derived endogenous metabolite kynurenic acid (KYNA) and of the lactam form of 3–2′-pyrrilonidinyl-kynurenic acid (3-PKA-L), alkaloids usually present in combination in chestnut honey. Cytotoxicity was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell colony formation assay, and Western blot analysis of the major mediator proteins involved in apoptotic processes. In all experiments, KYNA was scarcely or not active while 3-PKA-L showed anticancer activity in the high concentration range (0.01 mM – 1 mM) from 24 to 72 h. The results obtained showed that cell death was induced by extrinsic apoptotic pathway, by cell morphological changes and reduction of cell colonies number. These novel results represent the first promising step to the accurate description of 3-PKA-L cytotoxic effect, not observed with KYNA, paving the way to the search of new anticancer agents, as well as to the better understanding of the physiopathological role of this interesting natural product.
Highlights
Tryptophan is an important amino acid precursor of many biological processes, and the principal route of its catabolism is represented by the kynurenine pathway.Previous studies demonstrated that the kynurenine pathway deregulation can lead to cancer progression throughHandling editor: J
The results showed that 3-PKA-L was able to decrease the number of viable castration-resistant prostate cancer (CRPC) cells in a dose-dependent way, being significantly effective at 1 mM at all times evaluated; on the contrary, in our experimental condition, kynurenic acid (KYNA) did not significantly affect the growth of CRPC cells (Fig. 2a and Fig. 2b)
Cleaved PARP levels increased after 48 h and 72 h in DU145 cells and after 72 h in PC3 cells (Fig. 5b). These results indicated that apoptosis, through caspase 3 activation, were involved in 3-PKA-L cytotoxicity in CRPC cells
Summary
Tryptophan is an important amino acid precursor of many biological processes, and the principal route of its catabolism is represented by the kynurenine pathway.Previous studies demonstrated that the kynurenine pathway deregulation can lead to cancer progression throughHandling editor: J. Tryptophan is an important amino acid precursor of many biological processes, and the principal route of its catabolism is represented by the kynurenine pathway. Previous studies demonstrated that the kynurenine pathway deregulation can lead to cancer progression through. KYNA, the final metabolite of the kynurenine pathway, can be produced endogenously by different types of cells (Parada-Turska et al 2006; Kuc et al 2006; Paluszkiewicz et al 2009), and the initial studies regarding its biological role revealed neuroprotective and anticonvulsant properties (Scharfman et al 2000; Erhardt et al 2001; Chen et al 2011). In addition to its fundamental role as final tryptophanderived metabolite of the kynurenine pathway, it has been recognized as a robust marker of floral origin of sweet chestnut honey (Castanea sativa L.). Among all food types and all other honey types, shows the highest known KYNA content originating from the highly appetitive honeybee feeding sources C. sativa nectar and pollen
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