A Fumagillin Derivative Angiogenesis Inhibitor, AGM-1470, Inhibits Activation of Cyclin-dependent Kinases and Phosphorylation of Retinoblastoma Gene Product but not Protein Tyrosyl Phosphorylation or Protooncogene Expression in Vascular Endothelial Cells

Jun'ichi Abe, Wei Zhou, Yoh Takuwa

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

Abstract

Fumagillin analogue AGM-1470 potently inhibits angiogenesis with a minimal toxicity in vivo and is expected to be of therapeutic use as a powerful antitumor agent (Ingber et al., Nature, 348: 555-557, 1990). In the present study, we have investigated the effects and the mechanism of action of AGM-1470 on cultured human umbilical vein endothelial cells. AGM-1470 acts directly on endothelial cells to inhibit growth factorinduced DNA synthesis, with half maximal and maximal effects obtained at approximately 2 x 10-10 and 5 x 10-9 m, respectively. AGM-1470 does not inhibit early G1 mitogenic events, such as cellular protein tyrosyl phosphorylation or the expression of immediate early genes c-fos and c-myc, but potently inhibits phosphorylation of RB protein, a tumor suppressor retinoblastoma gene product The later addition of AGM-1470 up to 3 h after the growth factor stimulation still exerts fall inhibitory effects on both DNA synthesis and RB phosphorylation, suggesting that the major site of action of AGM-1470 is located relatively late in the G1 phase. AGM-1470 inhibits growth factor-induced activation of candidate RB kinases cdc2 and cdk2 but fails to inhibit them directly in vitro AGM-1470 completely abolishes the growth factor-induced mRNA expression of cdc2 and cyclin A and partially inhibits that of cyclin E but has little effect on the mRNA level of cdk2, cdk4, or cyclin D1. These results indicate that angioinhibitory action of AGM-1470 involves suppression of mRNA expression of specific members of cdks and cyclins and of activation of both cdc2 and cdk2 kinases in endothelial cells.

Original languageEnglish (US)
Pages (from-to)3407-3412
Number of pages6
JournalCancer Research
Volume54
Issue number13
StatePublished - Jul 1994
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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