Mechanism of Action of Granaticin: Inhibition of Ribosomal RNA Maturation and Cell Cycle Specificity

Abstract

Granaticin, an antibiotic produced by Streptomyces species was found to be cytotoxic (ED50 3.2 μg/ml) against human oral epidermoid carcinoma (KB) cells. At ED50 concentrations RNA synthesis was inhibited to the greatest extent. Prelabeling of RNA in KB cells, followed by addition of granaticin (2.13 μg/ml) showed that ribosomal RNA maturation was inhibited. The inhibition of the formation of functional ribosomal RNA was determined by sucrose gradient centrifugation and showed that the accumulation of 45S preribosomal RNA was dependent on granaticin concentration and on the time granaticin was in contact with the KB cells. The effect of granaticin (6.3 μg/ml) on KB cells in the different cell cycle phases showed preferential inhibition (93%) of cell survival in the G2 phase. However, RNA synthesis was only 20% inhibited by granaticin in KB cells in the G2 phase. From these results, it was concluded that ribosomal RNA maturation was not the only site of action of granaticin toxicity.