Dehydroleucodine inhibits tumor growth in a preclinical melanoma model by inducing cell cycle arrest, senescence and apoptosis.

COSTANTINO VV; LOBOS-GONZALEZ L; IBAÑEZ J; FERNANDEZ D; CUELLO-CARRIÓN FD; MANUEL A. VALENZUELA; BARBIERI MA; SEMINO SN; JAHN GA; QUEST AF; LOPEZ LA

CANCER LETTERS

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2016 vol. 372 p. 10 - 23

0304-3835

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 developmentof resistance to anti-neoplastic drugs remains the major cause of chemotherapy failure inmelanomas. Previously, we showed that the sesquiterpene lactone, dehydroleucodine (DhL), promotesthe accumulation of DNA damage markers, such as H2AX and 53BP1, in human tumor cells. Also DhLwas shown to trigger either cell senescence or apoptosis in a concentration-dependent manner in HeLaand MCF7 cells. Here, we evaluated the effects of DhL on B16F0 mouse melanoma cells in vitro and in apre-clinical melanoma model. DhL inhibited the proliferation of B16F0 cells by inducing senescence orapoptosis in a concentration-dependent manner. Also, DhL reduced the expression of the cell cycle proteinscyclin D1 and B1 and the inhibitor of apoptosis protein, survivin. In melanomas generated bysubcutaneous 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 apoptotictumor cells. To estimate the long-term effects of DhL, a mathematical model was applied to fit experimentaldata. Extrapolation beyond experimental time points revealed that DhL administration followingpreventive and therapeutic protocols is predicted to be more effective than simultaneous treatments withDhL in restricting tumor growth.