Novel strategies to deliver melatonin (in SLN and by cryo-laser therapy) to prostate cancer cells

Background: Melatonin (MT) is a chemical signal of dark/light, and serves as a bioclock and bio-calendar to mediate many receptor- or non receptor-mediated functions. MT also has a relevant oncostatic activity, especially with respect to prostate cancers, recently related to hypoxia and sphingolipids signaling pathways. The aims of the investigation are: to confirm that MT is active in the cure of prostate cancer, to speculate on the underlying mechanisms, to investigate the signaling pathways involved and to assess whether alternative and novel ways to deliver the drug may be competitive. Methods: We used an in vivo model of human prostate tumor LNCaP cells xenografted into nude athymic mice. MT has been administered i.p. as saline (n=13) and by SLN (solid lipid nanoparticles) (n=13) or transdermally by Cryopass therapy (n=14). For each treatment controls were also included. Each group received the same administration schedule: 3 treatments per week, for 6 week. At the end the animals were sacrificed and along the treatment period the mice weight were recorded as well as the tumor volume was measured. MT concentration was assessed in plasma and tissues by ELISA test and tumors were evaluated for morphology, MT content and HIF-1a expression. Results: Tumors developed slowly in all the MT-treated (topical and i.p.) groups and at the end of the treatment, the mean volume was significantly lower vs control. Both tumor and plasma levels were significantly higher in treated vs not-treated animals. Harvested tumor showed a strong inflammatory reaction which seemed to surround and infiltrate the tumor cells. In SLN-MT treated animals, in addition to a strong lymphocyte infiltration, the tumor appeared limited also by the presence of fibroblast type cells. Preliminary results showed HIF-1 expression increased in both treatment groups vs control. Conclusions: We have confirmed the positive effects of MT on tumor growth and we have focused on its effect on hypoxia. The possible role as anti-tumor drug candidate deserves to be further investigated. We demonstrated that different alternative and novel ways to deliver MT are effective as well. This would accelerate the transferability of obtained data towards a therapy. on MT oncostatic activity.