Morfina e tramadol na proliferação, apoptose e metástase pulmonar de células tumorais de melanoma in vitro e in vivo

Abstract

Morphine and tramadol are analgesic agents commonly employed in the management of cancer pain. Morphine, depending on factors, can inhibit or stimulate the growth of melanoma cells, but there is any data on tramadol. Therefore, the aim of the present study was to compare the effects of morphine and tramadol on melanoma cells in vitro and in vivo. B16F10 melanoma cells were exposed to different concentrations of morphine and tramadol (0.10, 0.50, 1.00, 2.00, 5.00; 10.00 μM) for 24 h. Cytotoxicity, viability, and cell death were evaluated using the MTT assay and Live/Dead. Events related to proliferative potential were evaluated using a colony formation assay. Additionally, C57Bl/6 mice were inoculated with B16F10 cells in the tail vein. After inoculation, the animals were distributed into groups of 6 animals each. The morphine group (GMOR) received morphine at a dose of 10 mg/kg, the tramadol group (GT) received tramadol at a dose of 50 mg/kg, and the control group (GC) received 0.1 mL of saline solution. Metastasis quantification was performed 21 days after inoculation. Both drugs, in a dose-dependent manner, were cytotoxic to B16F10 melanoma cells, reaching a maximum effect (80%) at 5.0 μM. However, at this concentration, morphine (49%) induced more apoptosis in cells than tramadol (37%). In the clonogenic test, tramadol (0.5 μM) inhibited the number of colonies formed by 80%, while morphine (0.5 μM) inhibited the formation of colonies by 100%. When administered at clinical doses, both morphine and tramadol significantly (p<0.05) decreased the formation of metastases in mice. However, morphine showed a greater reduction in lung tumorigenicity compared to tramadol (p<0.05). The association of tramadol at a clinical dose (2.00 μM) with cisplatin 0.0312 μM potentiated the inhibition of cell proliferation compared to cisplatin alone (p<0.05). In summary, the data from in vivo experiments indicated that both drugs induced a significant reduction in tumor size, as well as in the number of metastases. However, morphine was more effective than tramadol. Further research is needed to evaluate the antitumor effects of clinical doses of morphine and to explore the potential of tramadol as a substitute for morphine in the antitumor treatment and pain management of melanoma patients.