Abstract
Some diterpene glucosides produced by the plant‐pathogenic fungi are modulators of 14‐3‐3 proteins, and they induced the differentiation of human myeloid leukemia cells and apoptosis in human carcinoma cells in the presence of interferon‐alpha (IFN). Combined treatment with IFN and cotylenin A significantly inhibited the growth of human lung cancer cells as xenografts without apparent adeverse effects.
We synthesized several fusicoccin derivatives with antitumor activity, and found that some effective derivatives exhibited antitumor effects in xenografts inoculated with several human cancer cell lines when treated alone or with IFN. Among the derivatives, ISIR‐042 was the most effective in inhibition of the tumor growth in xenografts. This compound preferentially induced growth inhibition and apoptosis of some cancer cells under hypoxic conditions. The hypoxia‐targeting effects were not observed in the parental compound (cotylenin A) or other fusicoccin derivatives, suggesting that ISIR‐042 is the novel antitumor agent with a unique mode of action. Pancreatic cancer is highly aggressive and refractory to existing therapies.
Pancreatic ductal adenocarcinomas contain tumor cells that are at low oxygen tensions (hypoxic), and tumor hypoxia is known to induce the expression of a variety of genes associated with tumor progression and aggressiveness. Novel therapeutic strategies can be devised to improve treatment. Therefore, we examined the antitumor effect of ISIR‐042 with IFN in xenografts inoculated with human pancreatic cancer MiaPaCa‐2 cells. The combined treatment significantly inhibited the tumor growth in xenografts without appreciable adverse effects, suggesting that combined treatment with ISIR‐042 and IFN may have therapeutic value in treating pancreatic cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B156.
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