| dc.description.abstract | Malignant melanoma represents the fastest growing public health risk of all cancer types worldwide.
Several strategies and anti-cancer drugs have been used in an effort to improve treatments, but the development
of resistance to anti-neoplastic drugs remains the major cause of chemotherapy failure in
melanomas. Previously, we showed that the sesquiterpene lactone, dehydroleucodine (DhL), promotes
the accumulation of DNA damage markers, such as H2AX and 53BP1, in human tumor cells. Also DhL
was shown to trigger either cell senescence or apoptosis in a concentration-dependent manner in HeLa
and MCF7 cells. Here, we evaluated the effects of DhL on B16F0 mouse melanoma cells in vitro and in a
pre-clinical melanoma model. DhL inhibited the proliferation of B16F0 cells by inducing senescence or
apoptosis in a concentration-dependent manner. Also, DhL reduced the expression of the cell cycle proteins
cyclin D1 and B1 and the inhibitor of apoptosis protein, survivin. In melanomas generated by
subcutaneous injection of B16F0 cells into C57/BL6 mice, the treatment with 20 mg DhL /Kg/day in preventive,
simultaneous and therapeutic protocols reduced tumor volumes by 70%, 60% and 50%, respectively.
DhL treatments reduced the number of proliferating, while increasing the number of senescent and apoptotic
tumor cells. To estimate the long-term effects of DhL, a mathematical model was applied to fit experimental
data. Extrapolation beyond experimental time points revealed that DhL administration following
preventive and therapeutic protocols is predicted to be more effective than simultaneous treatments with
DhL in restricting tumor growth. | |
