Growth inhibition of hepatocellular carcinoma cells in vitro and in vivo by the 8-methoxy analog of WMC79.

Abstract

HKH40A (RTA 502), an optimized 8-methoxy analog of the unsymmetrical bifunctional antitumor agent WMC79, was found to be potently active against liver cancer cell growth in vitro and in vivo. Studies on selected human hepatocellular carcinoma (HCC) cell lines with differing p53 status (HepG2, Hep3B, and PLC/PRF/5), revealed that drug-mediated growth inhibition was independent of p53 status. FACS analysis showed an accumulation of cells in S-phase within 24 h of treatment with 100 nM HKH40A. Subsequent incubation of cells, either in the presence of drug or without, caused cell cycle block at the S and G2/M checkpoints, which was consistent with the observed up-regulation of p21, cyclin A, cyclin B1, sustained phosphorylation of Cdk1, and down-regulation of Cdc6, Cdc7, and RRM2. This irreversible growth arrest eventually led to apoptosis. HKH40A completely suppressed growth of the rat transplantable HCC cell line (JM-1) in an orthotopic model in Fisher 344 rats in vivo, without evidence of toxicity. HKH40A may be a useful agent for new therapeutic strategies focusing on inhibition of HCC cell proliferation.

• Authors: Teresa Kosakowska-Cholody, Wieslaw M Cholody, Humcha K Hariprakasha, Anne Monks, Siddhartha Kar, Meifang Wang, Christopher J Michejda, Brian I Carr
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 63 Issue 5 Pg. 769-78 (Apr 2009) ISSN: 1432-0843 [Electronic] Germany
• PMID: 18641988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Acridones
• Naphthalimides
• RTA 502
• Tumor Suppressor Protein p53

Topics

• Acridones (pharmacology)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Proliferation (drug effects)
• Humans
• In Vitro Techniques
• Liver Neoplasms, Experimental (drug therapy, pathology)
• Molecular Structure
• Naphthalimides (pharmacology)
• Rats
• Rats, Inbred F344
• S Phase (drug effects)
• Tumor Cells, Cultured (transplantation)
• Tumor Stem Cell Assay
• Tumor Suppressor Protein p53 (genetics, metabolism)