Citotoxicidade de lactonas sesquiterpênicas contra células de melanoma humano

Abstract

Cutaneous melanoma is the greater malignancy skin tumor that can display one of the worse prognoses due to its high mortality rate and invasive metastatic characteristics. Despite breakthrough advances in therapeutic strategies, limitations and disadvantages have been reported to the currently available drugs. Natural products have been a rich source of medicines for millennia, and several evidences have demonstrated promising pharmacological activities of the extracts of Tithonia diversifolia from which tagitinins are purified, especially attributed to tagitinin C (TC). Thus, the objective of this work was to check the in vitro cytotoxic properties of sesquiterpene lactone TC and its isomer, tagitinin F (TF), against human melanoma cells. For the experimental development of this study, cell viability assays were performed using the MTT and trypan blue exclusion test; the clonogenic assay was performed by violet crystal staining; the cell migration was performed by scratch technique and cell cycle and type of cell death analysis were performed by flow cytometer. TC and TF impair the growth of melanoma cells in a dose-dependent manner. TC showed cytotoxicity about 10 times greater than TF. At concentrations toxic to the CHL-1 line, TC and TF were not toxic to normal skin fibroblasts, whereas TF did not showed selectivity for WM1366. Cell migration was suppressed in a time-dependent manner, as well as cell proliferation. The substances inhibited the formation of colonies, which CHL-1 was more sensitive to the effects of TC and TF. Tagitinins promoted cell cycle arrest and induced apoptosis and necrosis. TF promoted cell-cycle arrest in the G2/M phase in 48 h. However, TC boosted arrest in G2/M at 24 h and sub-G1 distribution at 48 h. Both sesquiterpene lactones derived from Tithonia diversifolia showed a promising cytotoxic effect and selective tumor cell killing activity with the potential to negatively interfere with the complex oncogenic machinery.