N6‐isopentenyladenosine: A potential therapeutic agent for a variety of epithelial cancers

Abstract

Isopentenyladenosine (i6A) is a product of isopentenyltransferases and, in mammals, occurs either bound to tRNA or as a free nucleoside. Sporadic reports have suggested an anticancer effect of i6A, mostly on leukemia cells. The present analysis of 9 human epithelial cancer cell lines derived from different types of malignant tissue revealed complete suppression of clonogenic activity in 8 of the lines after exposure to i6A at a concentration of 10 μM. Mechanistic studies showed that i6A tumor suppressor activity is associated with inhibition of cell proliferation, a block in DNA synthesis and morphological changes. These results point to i6A and to its possible derivatives as a new potential class of wide‐spectrum anticancer agents. © 2007 Wiley‐Liss, Inc.

Pharmacogenomics and analogues of the antitumour agent N6‐isopentenyladenosine

“…Functional annotation of the modulated genes indicated alterations in the regulation of transcription, consistent with previous evidence of a role for i 6 A in RNA synthesis. 2,9 The significantly enriched GO term ''cell cycle arrest'' is consistent with evidence that i 6 A inhibits cell proliferation and negatively regulates cell cycle progression, 5,6 while the significant association with ''protein modification process'' could explain a previous finding of a role for i 6 A in inhibiting protein prenylation. 6 The association with apoptosis-related GO terms is also in accord with previous studies.…”

“…6 The association with apoptosis-related GO terms is also in accord with previous studies. 5,7,8 The significant association of our gene list with the GO term ''unfolded protein response'' suggests that i 6 A could exert its in vitro biological effects by inducing cellular stress associated with an accumulation of unfolded proteins. Unfolded proteins can be correctly refolded by chaperone proteins or degraded by the ubiquitin-proteasome pathway; when levels of misfolded proteins are excessive, cells can die.…”

“…7), the only cell line that was not completely inhibited by i 6 A treatment. 5 Effects of i 6 A and compound 1 on in vitro proliferation and on tumour-bearing mice Compound 1 inhibited both proliferation and DNA synthesis in A549 cells as measured using the AlamarBlue 1 assay and based on BrdU incorporation, but to a lesser extent than i 6 A. Indeed, proliferation at day 5 in cells treated with 10 lM i 6 A was inhibited (Fig.…”

“…These findings contrast with the complete inhibition of A549 clonogenicity by i 6 A at the same concentrations. 5 Compound 1 at 100 lM (the most effective dose in A549 cells) completely inhibited clonogenic activity in 6 cell lines tested (HepG2, IGROV1, MCF7, MDA-MB-361, NCI-H520 and NCI-H596), and induced approximately 5-and approximately 16-fold decrease in the number of Calu-3 and RPMI 2650 colonies, respectively (p < 0.0001). A slight but consistent inhibition of colony formation (less than 1.5-fold; p < 0.0001) was also observed in HT-29 cells (Fig.…”

“…4 We previously showed that i 6 A exerts potent in vitro antitumour activity on human epithelial cancer cell lines derived from different types of tumours. 5 Several i 6 A mechanisms of action have been hypothesized, including inhibition of cell proliferation, 5 inhibition of protein prenylation, 6 induction of apoptosis, 7,8 inhibition of DNA, RNA and/or protein synthesis, 2,9 and inhibition of nucleoside transport. 10,11 However, the precise mechanism of action of i 6 A in inhibiting cancer cell proliferation in vitro remains to be clarified.…”