Modulation of cancer pathways by inhibitors of guanylate metabolism

Edith Oláh, Szabolcs Kökény, János Papp, Anikó Bozsik, Márton Keszei

Research output: Article

16 Citations (Scopus)

Abstract

Cancer is generally thought to be the consequence of multiple genetic events. Metabolic imbalance is a cardinal feature of the malignant phenotype that has been shown to confer selective advantages to cancer cells (Weber, 1983). The elevated activity of guanylate synthetic pathways of cancer cells is due to increased activity of IMP dehydrogenase (EC 1.1.1.205) (IMP DH), the rate-limiting enzyme of GTP biosynthesis, therefore IMP DH was suggested and proven as a sensitive and selective target for enzyme-pattern-targeted chemotherapy. Clinically significant two nucleosides, tiazofurin and the antiviral agent ribavirin, were developed that exert antitumor activity in sensitive cells through inhibiting IMP DH activity and reducing GTP concentration. Here we report and review the molecular impact of targeting IMP DH with these two drugs. The focus is on genes that are key components of cancer pathways. Using tiazofurin we presented the first evidence that IMP inhibitors may act, in part at least, by down-regulation of oncogene expression (this was observed on the GTP requiring RAS oncogene and the transcription factor c-MYC) (Olah et al., 1988). We show that the down-regulation of oncogenes by either tiazofurin or ribavirin in different cancer cell lines similarly induces cell-cycle arrest, differentiation and apoptosis. Apoptosis seemed to have a major role in the action of ribavirin, whereas differentiation appeared to be more important in the anticancer effect of tiazofurin. Tiazofurin, as compared to other anticancer drugs, proved to be the most potent inducer of differentiation toward the erythroid pathway in BCR-ABL positive K562 leukemia cells. On the basis of our current and previous results it appears that the same sequence of events prepares cells for the program of differentiation and apoptosis induced by either tiazofurin or ribavirin. This starts with early metabolic changes (decreases in IMP dehydrogenase activity and in GTP concentration) and with early marked down-regulation of MYC oncogene (and RAS by tiazofurin). Preliminary results of oligo microarray analysis and quantitative real-time PCR have revealed that the molecular action of ribavirin also leads to a marked early (t1 / 2 = 0.5-6 h) effect on gene expression modulating over 2600 known genes (at p < 0.01) with a significant difference of expression between the ribavirin treated and the untreated K562 cells. Affected pathways-among others-are apoptosis, integrin-mediated adhesion, and those including chemokine family and PI3K (phosphoinositide 3-kinase). Though further studies are needed to identify the key target genes and mechanisms of drug action, these preliminary results and other reported data suggest that ribavirin-similarly to tiazofurin-should be effective against various tumor cells through interfering with key signaling pathways. In addition, the presented data provide evidence that IMP DH remains an attractive target for cancer chemotherapy in the emerging era of targeted molecular cancer therapy.

Original languageEnglish
Pages (from-to)176-190
Number of pages15
JournalAdvances in Enzyme Regulation
Volume46
Issue number1
DOIs
Publication statusPublished - szept. 4 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research

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