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.

Keywords:

• Chromomycins
• secondary metabolites
• anticancer
• non-small cell lung cancer cells
• c-FLIP

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by grants from CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-1-I2M-030, and 2022-I2M-1-016), Beijing Natural Science Foundation (7202132), and the National Natural Science Foundation of China (Grant nos. 82273830).