Inhibition of protein synthesis and cell proliferation in cultured human breast cancer cells treated with mitoxantrone.

Mitoxantrone suppresses cell proliferation, inhibits protein synthesis and induces ultrastructural alterations in the T-47D and MDA-MB-231 breast cancer cell lines. After 24 h treatment with 10(-9), 10(-7) and 10(-5) M drug and 8 h incubation with [35S]methionine, protein synthesis declined rapidly. While a 10-15% decrease in protein synthesis at 10(-9) M was observed, more than 95% inhibition of protein synthesis occurred at 10(-5) M mitoxantrone in both cell lines. Sodium dodecylsulfate (SDS) gel electrophoresis of labeled proteins revealed no qualitative changes in either cell line. However, only trace amounts of several proteins were present in T-47D cells treated with 10(-5) M drug. At 10(-9) M mitoxantrone had little effect on cell proliferation. At 10(-7) M, 25% and 35% growth inhibition in T-47D and MDA-MB-231 cells was observed, respectively. Cell growth at 10(-5) M was abolished. Cytotoxicity was evident at drug concentrations above 10(-5) M. Ultrastructural alterations in the nucleoli of both cell lines included disintegration and segregation of granular and fibrillar components and the disappearance of nucleolar organizers at 10(-7)-10(-5) M mitoxantrone.