Consequences of IMP dehydrogenase inhibition, and its relationship to cancer and apoptosis

Inosine 5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme fo r the synthesis of GTP and dGTP. Two isoforms of IMPDH have been identified . IMPDH Type I is ubiquitous and predominantly present in normal cells, whe reas IMPDH Type II is predominant in malignant cells. IMPDH plays an import ant role in the expression of cellular genes, such as p53, c-myc and Ki-ras . IMPDH activity is transformation and progression linked in cancer cells. IMPDH inhibitors, tiazofurin, selenazofurin, and benzamide riboside share s imilar mechanism of action and are metabolized to their respective NAD anal ogues to exert antitumor activity. Tiazofurin exhibits clinical responses i n patients with acute myeloid leukemia and chronic myeloid leukemia in blas t crisis. These responses relate to the level of the NAD analogue formed in the leukemic cells. Resistance to tiazofurin and related IMPDH inhibitors relate mainly to a decrease in NMN adenylyltransferase activity. IMPDH inhb itors induce apoptosis. IMPDH inhitors are valuable probes for examining bi ochemical functions of GTP as they selectively reduce guanylate concentrati on. Incomplete depletion of cellular GTP level seems to down-regulate G-pro tein function, thereby inhibit cell growth or induce apoptosis. Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes the dehydrogenation of IMP to XMP utilizing NAD as the proton acceptor. Studies have demonstrated that IMPDH is a rate-limiting step in the de novo synthe sis of guanylates, including GTP and dGTP. The importance of IMPDH is centr al because dGTP is required for the DNA synthesis and GTP plays a major rol e not only for the cellular activity but also for cellular regulation. Two isoforms of IMPDH have been demonstrated [1]. IMPDH Type I is ubiquitous an d predominately present in normal cells, whereas the IMPDH Type II enzyme i s predominant in malignant cells [2]. Although guanylates could be salvaged from guanine by the enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the level of circulating guanine is low in dividing cells and this route is probably insufficient to satisfy the needs of guanylates in the cells [3].