Consequences of IMP dehydrogenase inhibition, and its relationship to cancer and apoptosis.
Inosine 5 -monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme for the synthesis of GTP and dGTP. Two isoforms of IMPDH have been identified. IMPDH Type I is ubiquitous and predominantly present in normal cells, whereas IMPDH Type II is predominant in malignant cells. IMPDH plays an important 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 similar mechanism of action and are metabolized to their respective NAD analogues to exert antitumor activity. Tiazofurin exhibits clinical responses in patients with acute myeloid leukemia and chronic myeloid leukemia in blast 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 inhbitors induce apoptosis. IMPDH inhitors are valuable probes for examining biochemical functions of GTP as they selectively reduce guanylate concentration. Incomplete depletion of cellular GTP level seems to down-regulate G-protein 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 synthesis of guanylates, including GTP and dGTP. The importance of IMPDH is central because dGTP is required for the DNA synthesis and GTP plays a major role not only for the cellular activity but also for cellular regulation. Two isoforms of IMPDH have been demonstrated. IMPDH Type I is ubiquitous and predominately present in normal cells, whereas the IMPDH Type II enzyme is predominant in malignant cells. 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.
Jayaram
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Department of Biochemistry and Molecular Biology and Laboratory for Experimental Oncology, Indiana University School of Medicine, 699 West St., Indianapolis, IN 46202-5119, USA.
Cooney
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Grusch
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Krupitza
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002986:Clinical Trials as Topic; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006160:Guanosine Triphosphate / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007951:Leukemia, Myeloid / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy; D009705:Nucleosides / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology / Q000633:toxicity; D012263:Ribonucleosides / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D012263:Ribonucleosides; C076145:3-(1-deoxyribofuranosyl)benzamide; D012254:Ribavirin; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; C517004:CDC25A protein, human; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases; C039064:selenazofurin; C033706:tiazofurin