ABSTRACT
BACKGROUND AND PURPOSE: No current treatment reliably affects the course of metastatic melanoma. Consequently, novel approaches to the control of metastasis are actively sought. The overall goal of the present study was to identify new anti-metastatic agents active against melanoma cells. EXPERIMENTAL APPROACH: Two directions were taken: 1. To determine whether the natural plant hormone methyl jasmonate, which kills cancer cells selectively, can suppress the characteristic metastatic behavior of B16-F10 melanoma cells; 2. To synthesize and identify novel jasmonate derivatives with better cytotoxic and anti-metastatic activities than methyl jasmonate. KEY RESULTS: We found that methyl jasmonate suppressed B16-F10 cell motility and inhibited the development of experimental lung metastases of these cells. Furthermore, methyl jasmonate suppressed the motility of a sub-clone of these cells over-expressing P-glycoprotein and exhibiting multidrug resistance. The synthetic derivative Compound I (5,7,9,10-tetrabromo derivative of methyl jasmonate, the most active derivative) had greater cytotoxic potency (IC(50), 0.04 mM) than methyl jasmonate (IC(50), 2.6mM). Compound I prevented B16-F10 cell adhesion efficiently and inhibited the development of lung metastases at a much lower dose than methyl jasmonate. CONCLUSIONS AND IMPLICATIONS: Natural and synthetic jasmonates have anti-metastatic actions. Further development of these agents for the suppression of metastasis in melanoma and other types of cancer is warranted.
