A novel pyrrolidine-2,5-dione derivative induced G2/M phase arrest and apoptosis of hepatocellular carcinoma HepG2 cells through inhibiting tubulin polymerization

Abstract

Hepatocellular carcinoma (HCC) is a major global cause of carcinoma-related fatality. The inhibition of tubulin polymerization holds significant potential in the development of cancer drugs. In our study, we synthesized a novel pyrrolidine-2,5-dione derivative (compound 8) that exhibited potent anti-HCC activity (IC50 value of 2.082 μM) against human HCC HepG2 cells. Moreover, compound 8 significantly suppressed the HepG2 cell multiplication, and triggered G2/M phase arrest of HepG2 cells and their apoptosis. Further mechanistic investigations revealed that compound 8 suppressed tubulin polymerization by directly binding to the colchicine binding site of β-tubulin. Additionally, compound 8 significantly inhibited tumor growth with low toxicity in nude HepG2 tumor-bearing mice, achieving an approximate inhibition rate of 45.73 %. Therefore, compound 8 represents a promising pharmaceutical candidate for HCC management.

Keywords

• Pyrrolidine-2,5-dione derivative
• Hepatocellular carcinoma
• Proliferation
• G2/M phase arrest
• Apoptosis
• Tubulin polymerization