Abstract
The morphological transformation of Trypanosoma cruzi amastigotes was studied in both mammalian cells and an extracellular differentiation system. Inhibitors of ADP-ribosyl transferase were found to block differentiation in both cases, without affecting proliferation. The inhibitory effect was reversible and was not observed with chemical analogues that do not inhibit ADP-ribosyl transferase. As inhibitors of ADP-ribosyl transferase have recently been shown to block the differentiation of several cell types from vertebrates (Farzaneh, F., R. Zalin, D. Brill, and S. Shall, 1982, Nature (Lond.), 300:362-366; Johnstone, A. P., and G. T. Williams, 1982, Nature (Lond.), 300:368- 370), our results suggest that the enzyme is of general importance in eucaryotic differentiation both in multicellular and unicellular organisms. In addition, since the compounds can block T. cruzi differentiation inside mammalian cells, these results suggest that it may be possible to exploit such inhibition in a new and potentially powerful approach to the chemotherapy of several important parasitic diseases.
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Selected References
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- Althaus F. R., Lawrence S. D., He Y. Z., Sattler G. L., Tsukada Y., Pitot H. C. Effects of altered [ADP-ribose]n metabolism on expression of fetal functions by adult hepatocytes. Nature. 1982 Nov 25;300(5890):366–368. doi: 10.1038/300366a0. [DOI] [PubMed] [Google Scholar]
- Baker J. R., Price J. Growth in vitro of Trypanosoma cruzi as amastigotes at temperatures below 37degrees C. Int J Parasitol. 1973 Jul;3(4):549–551. doi: 10.1016/0020-7519(73)90053-2. [DOI] [PubMed] [Google Scholar]
- Brener Z. Biology of Trypanosoma cruzi. Annu Rev Microbiol. 1973;27:347–382. doi: 10.1146/annurev.mi.27.100173.002023. [DOI] [PubMed] [Google Scholar]
- Caplan A. I., Ordahl C. P. Irreversible gene repression model for control of development. Science. 1978 Jul 14;201(4351):120–130. doi: 10.1126/science.351805. [DOI] [PubMed] [Google Scholar]
- Caplan A. I., Rosenberg M. J. Interrelationship between poly (ADP-Rib) synthesis, intracellular NAD levels, and muscle or cartilage differentiation from mesodermal cells of embryonic chick limb. Proc Natl Acad Sci U S A. 1975 May;72(5):1852–1857. doi: 10.1073/pnas.72.5.1852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clark J. B., Ferris G. M., Pinder S. Inhibition of nuclear NAD nucleosidase and poly ADP-ribose polymerase activity from rat liver by nicotinamide and 5'-methyl nicotinamide. Biochim Biophys Acta. 1971 Apr 29;238(1):82–85. doi: 10.1016/0005-2787(71)90012-8. [DOI] [PubMed] [Google Scholar]
- Farzaneh F., Zalin R., Brill D., Shall S. DNA strand breaks and ADP-ribosyl transferase activation during cell differentiation. Nature. 1982 Nov 25;300(5890):362–366. doi: 10.1038/300362a0. [DOI] [PubMed] [Google Scholar]
- Johnstone A. P., Williams G. T. Role of DNA breaks and ADP-ribosyl transferase activity in eukaryotic differentiation demonstrated in human lymphocytes. Nature. 1982 Nov 25;300(5890):368–370. doi: 10.1038/300368a0. [DOI] [PubMed] [Google Scholar]
- Levi V., Jacobson E. L., Jacobson M. K. Inhibition of poly(ADP-ribose) polymerase by methylated xanthines and cytokinins. FEBS Lett. 1978 Apr 1;88(1):144–146. doi: 10.1016/0014-5793(78)80627-9. [DOI] [PubMed] [Google Scholar]
- Mandel P., Okazaki H., Niedergang C. Poly(adenosine diphosphate ribose). Prog Nucleic Acid Res Mol Biol. 1982;27:1–51. doi: 10.1016/s0079-6603(08)60596-6. [DOI] [PubMed] [Google Scholar]
- Okolie E. E., Adewunmi A. I., Enwonwu C. O. Antimalarial activity of inhibitors of ADP-ribosyl transferase against Plasmodium yoelii infection in mice. 1. Preliminary data. Acta Trop. 1982 Sep;39(3):285–287. [PubMed] [Google Scholar]
- Okolie E. E., Onyezili N. I. ADP-ribosyltransferase in Plasmodium (malaria parasites). Biochem J. 1983 Mar 1;209(3):687–693. doi: 10.1042/bj2090687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pan C. T. Cultivation and morphogenesis of Trypanosoma cruzi in improved liquid media. J Protozool. 1971 Nov;18(4):556–560. doi: 10.1111/j.1550-7408.1971.tb03375.x. [DOI] [PubMed] [Google Scholar]
- Purnell M. R., Stone P. R., Whish W. J. ADP-ribosylation of nuclear proteins. Biochem Soc Trans. 1980 Apr;8(2):215–227. doi: 10.1042/bst0080215. [DOI] [PubMed] [Google Scholar]
- Purnell M. R., Whish W. J. Novel inhibitors of poly(ADP-ribose) synthetase. Biochem J. 1980 Mar 1;185(3):775–777. doi: 10.1042/bj1850775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rastl E., Swetly P. Expression of poly(adenosine diphosphate-ribose) polymerase activity in erythroleukemic mouse cells during cell cycle and erythropoietic differentiation. J Biol Chem. 1978 Jun 25;253(12):4333–4340. [PubMed] [Google Scholar]
- Sanderson C. J., Thomas J. A., Twomey C. E. The growth of Trypanosoma cruzi in human diploid cells for the production of trypomastigotes. Parasitology. 1980 Feb;80(1):153–162. doi: 10.1017/s0031182000000615. [DOI] [PubMed] [Google Scholar]
- Tsopanakis C., Leer J. C., Nielsen O. F., Gocke E., Shall S., Westergaard O. Poly (ADP-Ribose) metabolizing enzymes in nuclei and nucleoli of Tetrahymena pyriformis. FEBS Lett. 1978 Sep 15;93(2):297–300. doi: 10.1016/0014-5793(78)81125-9. [DOI] [PubMed] [Google Scholar]
- WARREN L. G. Metabolism of Schizotrypanum cruzi Chagas. I. Effect of culture age and substrate concentration on respiratory rate. J Parasitol. 1960 Oct;46:529–539. [PubMed] [Google Scholar]
- Williams G. T. Trypanosoma cruzi: inhibition of intracellular and extracellular differentiation by ADP-ribosyl transferase antagonists. Exp Parasitol. 1983 Dec;56(3):409–415. doi: 10.1016/0014-4894(83)90086-3. [DOI] [PubMed] [Google Scholar]