6,7-dihydroxy-3,4-dihydroisoquinoline: a novel inhibitor of nuclear factor-kappaB and in vitro invasion in murine mammary cancer cells.

Abstract

BACKGROUND: The inhibition of nuclear factor (NF)-kappaB with nontoxic agents is a promising possible treatment approach that may inhibit tumor cell proliferation, counteract the prosurvival pathways that mediate resistance to cytotoxic therapy, and prevent tumor cell metastasis. METHODS: An initial structure-activity relationship study of the NF-kappaB inhibitory activity of acetophenone-type compounds using electrophoretic mobility shift assay and Western blot analysis is presented. An in vitro cell invasion assay using DA3 cells, a murine breast cancer cell line, was conducted to model antimetastatic activity. RESULTS: The carbonyl moiety is found to be the functional group responsible for inhibition of NF-kappaB, and a novel, more effective agent, 6,7-dihydroxy-3,4-dihydroisoquinoline, is postulated and confirmed. The compounds are characterized as active in the inhibition of both the canonical and noncanonical NF-kappaB signaling pathways. Lastly, 6,7-dihydroxy-3,4-dihydroisoquinoline is discovered to inhibit in vitro invasion in DA3 cells. CONCLUSION: 6,7-Dihydroxy-3,4-dihydroisoquionoline and its derivatives are presented as potential prototypes for a novel series of nontoxic antimetastatic agents that can be used in conjunction with current cancer therapeutic techniques.