Chromomycins from soil-derived Streptomyces sp. inhibit the growth of human non-small cell lung cancer cells by targeting c-FLIP.

Abstract

Three chromomycin derivatives, chromomycins A₃ (1, CA₃), A₅ (2, CA₅), and monodeacetylchromomycin A₃ (3, MDA-CA₃), were identified from the soil-derived Streptomyces sp. CGMCC 26516. A reinvestigation of the structure of CA₅ is reported, of which the absolute configuration was unambiguously determined for the first time to be identical with that of CA₃ based on nuclear magnetic resonance (NMR) data analysis as well as NMR and electronic circular dichroism calculations. Compounds 1-3 showed potent cytotoxicity against the non-small-cell lung cancer (NSCLC) cells (A549, H460, H157-c-FLIP, and H157-LacZ) and down-regulated the protein expression of c-FLIP in A549 cells. The IC₅₀ values of chromomycins in H157-c-FLIP were higher than that in H157-LacZ. Furthermore, si-c-FLIP promoted anti-proliferation effect of chromomycins in NSCLC cells. In nude mice xenograft model, 1 and 2 both showed more potent inhibition on the growth of H157-lacZ xenografts than that of H157-c-FLIP xenografts. These results verify that c-FLIP mediates the anticancer effects of chromomycins in NSCLC.